2,3-cis-Cyclization of 4-pentenoxyl radicals

Tetrahedron 72 (2016) 7699e7714

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2,3-cis-Cyclization of 4-pentenoxyl radicals €ßer, Irina Kempter, Christine Schur, Katharina Huttenlochner, Ruth-Maria Bergstra Benjamin Wolff, Thomas Kopf, Jens Hartung * €t Kaiserslautern, Erwin-Schro €dinger-Straße, D-67663 Kaiserslautern, Germany Fachbereich Chemie, Organische Chemie, Technische Universita

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 February 2016 Received in revised form 28 June 2016 Accepted 1 July 2016 Available online 7 July 2016

4-Pentenoxyl radicals cyclize 2,3-cis-selectively, when substituted by an allylic hydroxy, acetyloxy, or benzoyloxy group. Additional substituents increase or decrease the fraction of 2,3-cis-cyclized product, depending on relative configuration, positioning, and their chemical nature. The preference for 3acceptor-subsituted pentenoxyl radicals to furnish products of 2,3-cis-ring closure arises from a secondary orbital interaction between the allylic oxygen substituent and the alkene entity, kinetically disfavoring the 2,3-trans-mode of 5-exo-cyclization. Aligning the b-C,O-bond in anticline orientation to the plane of the alkene, which is the preferred conformation for transition structures for 2,3-trans-cyclization, stabilizes the double bond by delocalizing p-electrons into the s*(C,O)-orbital. Along with energy decreases the affinity of p-electrons for forming a s (C,O)-bond with the oxygen radical. In 2,3-cis-cyclization, a similar stabilizing effect cannot occur, because the allylic oxygen substituent and the alkene align synperiplanar. The kinetic effect of an allylic oxygen substituent becomes furthermore apparent in cyclization of the 3-hydroxynona-1,8-dien-5-oxyl radical, favoring intramolecular addition to the unsubstituted allylic double bond by a factor three. Ó 2016 Elsevier Ltd. All rights reserved.

Keywords: Alkoxyl radical Polar effect Reactive conformer Stereoselective synthesis Tetrahydrofuran

1. Introduction 4-Pentenoxyl radicals cyclize 2,3-trans-selectively when substituted with an allylic alkyl or a phenyl group (Scheme 1).1 The fraction of 2,3-trans-product increases with the size of the allylic substituent, from 80/20 for methyl to above 99/1 for tert-butyl.2,3 Transition state theory4 explains 2,3-trans-selectivity on the basis of cumulative 1,2- and 1,3-repulsion, progressively disfavoring 2,3cis-addition as steric demand of the allylic substituent grows.5,6

O

H • CH2 H Ph

2,3-trans

X = Ph H R=H R O•

X = OH R = CH3

X

dr = 5:95

H

O

H • CH2 H OH

2,3-cis dr = 70:30

Scheme 1. Stereoselectivity in 5-exo-cyclization of allyl-substituted 4-pentenoxyl radicals.2,3,7

* Corresponding author. Tel.: þ49 631 205 2431; fax: þ49 631 205 3921; e-mail address: [email protected] (J. Hartung). http://dx.doi.org/10.1016/j.tet.2016.07.001 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

Steric effects controlling selectivity in synthesis of 2,3-transsubstituted heterocycles by intramolecularly adding polar reactands11,12 or radicals13e17 to double bonds are well documented in the scientific literature. In the past decades, however, more and more reports appeared describing selectivity not fitting into this stereochemical scheme. Alkenols bearing an allylic oxygen substituent, for example, show a marked propensity for cyclizing 2,3cis-selectively, when treated with molecular iodine. A theory explaining this phenomenon starts to evolve, but is not yet consistent.18e21 The affinity of the allylic hydroxy group to direct cyclizations 2,3-cis-selectively also extends to oxygen radical additions, as recently outlined in synthesis of allo-isomuscarine (Scheme 1, Fig. 1).8 The alkene in this example poses the nucleophilic component and the radical oxygen the electrophilic, which is exactly opposed to the situation in electrophile-induced alkenol cyclization. A theory explaining 2,3-cis-selectivity in radical cyclization so far does not exist. For uncovering the principles leading to 2,3-cis-selective ring closures, we investigated in the study summarized below, reactivity and selectivity of 4-pentenoxyl radicals, differing in substitution at the allylic carbon and at proximal positions (Fig. 2). The results from this effort show that an allylic oxygen substituent reduces the rate of intramolecular 2,3-trans-addition, and leave the rate of the 2,3cis-pathway largely unaffected. The rate effect of the allylic oxygen

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H

O 2

+ H N(CH3)3

F H

F

H OH

H HO

O 3

O R

3

–

O O O O H P P O– O O O H H 3 2 O H H N OH HO H H HO OH

HO H HO

O• H

Ia Ib Ic

Ac Bz

OAc

erythro-Id I

O•

AcO OAc

R

Ie H

O•

AcO OAc threo-Id

S O

5

• CH2

OR1

H

OR1 1

exo

II

O•

Ia–c

• CCl3

R2

substituent is not restricted to stereocontrol but also controls selectivity in intramolecular addition of an oxyl radical to two chemically different C,C-double bonds. The 3-hydroxynona-1,8dien-5-oxyl radical thus prefers adding to the unsubstituted allylic double bond by a partial rate factor three.

AcO

OR1

O

Fig. 1. Structure formulas of bio-inspired 2- and 3-hydroxy-substituted tetrahydrofurans as targets in organic synthesis.8e10

OR

R2

BrCCl3

N

UDP-C-D-galactofuranose

O•

S

N O

Br

2

thymidine bioisoster

allo-isomuscarine

S

H OH

OH rel-(3R,5S)-If

Fig. 2. Structure formulas of 4-pentenoxyl radicals Iaef conceived for uncovering the origin of 2,3-cis-selectivity in homolytic 5-exo-cyclization.

O• R2

trig(onal)

N

SCCl3

2

OR1 I

Scheme 2. Chain reaction for bromomethyltetrahydrofuran synthesis from 3alkenoxy-4-methylthiazole-2(3H)-thione 1 and BrCCl3 (R1¼H, Ac, Bz; R2¼H, OAc, CH3).8,24

terms of regioselectivity the intramolecular addition should lead to a 5-exo/6-endo-distribution ranging from 98:2 (for X¼CH3) to 90:10 (for X¼OH).27 For terminating the sequence, cyclized radical II needs to be trapped by a mediator. In the present study, we used bromotrichloromethane for this purpose, providing 2bromomethyltetrahydrofuran 3 as major oxygen radical-derived product.8 The requested information on stereocontrolling effects of oxygen substituents in cyclizations then is stored in the cis/ trans-ratio of bromocyclization product 3. The second product of bromine atom transfer from bromotrichloromethane to carbon radical II is the trichloromethylradical, being essential for resuming the chain reaction. For clarifying the role of the allylic oxygen substituent in stereoselectivity control for alkenoxyl radical 5-exo-cyclization, we conceived a set of six alkenoxyl radicals: three monosubstituted 4pentenoxyl radicals (Iaec), two homologues bearing acetyloxy groups in different relative configuration (erythro/threo-Id), and a third (Ie) having an allylic acyloxy group positioned next to two additional substituents (Fig. 2). As we became aware of the kinetic role of the allylic oxygen substituent, we included nonadienyloxyl radical If into the study, for exploring regioselectivity effects. 2.2. Convention used for numbering atom positions

2. Results and interpretation 2.1. Alkenoxyl radical generation, chain reaction, and design of alkenoxyl radicals for conducting the study Based on the expertise from preceding mechanistic studies,8,22 we used O-pentenyl esters of 1,3-thiazole-derived heterocyclic thiohydroxamic acids23 as progenitors for generating oxygen radicals. Heating compounds of this kind, for example the 3-alkoxy-1,3thiazole-2(3H)-thiones,1 in the presence of a chemical initiator, or photoexciting the molecules with 350 nm-light, almost specifically breaks the N,O-bond, allowing to liberate oxygen radicals under pH-neutral and non oxidative conditions from otherwise stable compounds. The mechanism operating for converting 3-alkoxy-1,3thiazole-2(3H)-thiones into alkoxyl radicals is a chain reaction. The sequence starts by adding a chain propagating radical to the thione sulfur of the thiohydroxamate used as progenitor, providing oxygen radical I and substituted thiazole 2 (Scheme 2).24 By extrapolating known kinetic data,2,25,26 we expect allylsubstituted derivatives to intramolecularly add with a rate constant between 108 s1 and 109 s1 to the C,C-double bond. In

Oxygen and carbon differ in priority for systematically naming aliphatic and heterocyclic compounds. For carbons in the aliphatic side chain of O-alkenyl ester 1, and for the carbons of radical I, we adhered to the IUPAC-recommendation for aliphatic compounds.28 A transition structure TS-I associated with 5-exo-cyclization, in the chosen stereochemical model, derives from tetrahydrofuran (cf. Section 2.5.3). Numbering atoms in intermediate TS-I, similar to tetrahydrofuran core of cyclized carbon radical II, and bromocyclization product 3 thus follows the Hantzsch and Widman convention (Fig. 3).29,30 For assigning configuration of vicinal stereocenters, we adhered in this article to descriptors erythro and threo. By this approach we feel, that the reader may easier follow differences in chemical selectivity, as configuration at one of the stereocenters changes. 2.3. 3-Alkenoxy-4-methylthiazole-2(3H)-thiones 2.3.1. Monosubstituted O-pentenyl thiohydroxamates. For constructing the alkenoxy group of thiohydroxamate 1a, we connected in the initial step ethyl acetate to acrolein by a mixed aldol addition (Scheme 3).31,32 The product formed in the addition, ethyl 3-

I. Kempter et al. / Tetrahedron 72 (2016) 7699e7714

1 2

OMTT 4

3

5

1

O•

1

3

2

OH

OH

1a

Ia

4

2

5

1

O• 3

7701

5 4

• O 5 CH 2

2 3

OH

4

OH

1

O 5

2 3

OH

3a

IIa

TS-Ia

4

Br

Fig. 3. Convention used in this article for numbering atoms in product classes associated with alkenoxyl radical cyclization, as exemplified for alkenoxythiazolethione 1a, derived 4alkenoxyl radical Ia, transition structure for 5-exo-cyclization TS-Ia, 5-exo-cyclized carbon radical IIa, and bromocyclization product 3a (MTT¼4-methyl-2-thiooxo-1,3-thiaz-3-yl).

hydroxypentenoate, eliminates water on standing. For preventing this elimination to occur, we converted the reactive hydroxy group into a methoxymethyloxy (MOMO)-group.32,33 Subsequently, we transformed the ethoxycarbonyl group in ester 4 into primary alkyl sulfonate group in tosylate 5 by standard procedures.32,34 Displacing the sulfonate group in tosylate 5 by the 4-methyl-2thiooxo-(3H)-1,3-thiazyl-1-oxide anion furnishes a MOMprotected O-alkenyl thiohydroxamate, which was treated with hot acidic methanol for solvolytically cleaving off the acetalprotecting group. Esterifying the hydroxy group in alcohol 1a with acetic anhydride gives acetate 1b. Using benzoyl chloride as acylation reagent provides benzoate 1c (Scheme 4).

OEt

O

acrolein O

2.

1. Na2CO3 / H2O2 2. MeO OMe HO

H

O

HO HO

1. LDA / THF O

treated with methanediyltriphenylphosphorous ylide to furnish alkenol erythro-6.35e37 For converting alkenol erythro-6 into Oalkenyl thiohydroxamate erythro-7, we adhered to methods already summarized in Scheme 3.24,38,39 At the final stage, we again changed protecting groups at oxygen from acetonide, required for synthesis, to acyl required for alkenoxyl radical cyclization.40

O OH

OEt D-isoascorbic acid

O

P2O5

O

TsOH 3. NaBH4 / H2O + 4. Ph3PCH3 Br – KOtBu / THF

O

3. LiAlH4 / Et2O OMTT

4. TsCl / DABCO OMTT

4

DMF

OTs

AcO 2

OH 1a (72%)

O

O

erythro-1d (74%)

5 (77%)

Scheme 3. Summary of functional group transformation for preparing 3-(3hydroxypent-4-enyloxy)thiazolethione 1a from ethyl acetate (MTTO¼4-methyl-2thiooxo-1,3-thiazyl-3-oxy; cf. Fig. 3).

OMTT 3

Ac2O / NEt3 DMAP CH2Cl2

3

OAc

3

6. HCl / CH3OH

OMTT 3

BzCl / NEt3 DMAP CH2Cl2

erythro-6 (32%) 5. TsCl / DABCO 6. MTTO – NEt4+

4 (43%)

5. MTTO– NEt +

OH H 3 O 2 H O

OMTT 3

OAc

OH

OBz

1b (82%)

1a

1c (52%)

Scheme 4. O-Acylation of 3-(3-hydroxypent-4-enyloxy)thiazolethione 1a.

2.3.2. Disubstituted O-pentenyl thiohydroxamates. For preparing the erythro-configured side chain of O-(2,3-erythro-bisacetyloxypentenyl) thiohydroxamate erythro-1d, we started from Derythronolactone. The lactone is synthetically available from Disoascorbic acid by oxidatively removing two carbon atoms (Scheme 5). For preventing oxidative side reactions, we protected the two hydroxy groups of the lactone with 2,2dimethoxypropane in acidic solution under kinetic control, leading to the derived acetonide.35 Reducing the protected D-erythronolactone with sodium borohydride affords a lactol, which was

7. HCl / MeOH 8. Ac2O / NEt3

OMTT H 3 O 2 H O erythro-7 (48%)

Scheme 5. Preparing of 3-[2,3-erythro-2,3-bis-(acetyloxy)pent-4-en-1-oxy]thiazolethione erythro-1d from D-isoascorbic acid.

For preparing O-(threo-2,3-bisacetyloxypentenyl) thiohydroxamate threo-1d, we used dimethyl (2R,3R)-tartrate as starting material. The ester comprises two stereocenters in the required configuration and two functional groups for building the carbon skeleton of target compound threo-1d. One of the ester groups served in a sequence adapted from synthesis of diastereomer erythro-1d for introducing the thiohydroxamate functional group at a primary carbon. The second ester group was used for constructing the alkene entity needed for conducting the alkenoxyl radical cyclization. By this strategy, we obtained monosilylprotected diol threo-8 as first key intermediate, acetonideprotected 4-pentenetriol threo-6 as second and O-alkenyl thiohydroxamate threo-1d as final product41e45(Scheme 6). 2.3.3. Trisubstituted O-pentenyl thiohydroxamate 1e. For accomplishing synthesis of D-arabino-configured thiohydroxamate 1e we extended the five carbon chain from D-ribose by one carbon in a Wittig-alkenylation, and inverted configuration at carbon C2 in the thiohydroxamate O-alkylation step (Scheme 7). For simplifying work-up procedures we, again, used the acetonide protecting group for the glycol segment. The thiohydroxamic acid we changed to 3hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione,

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I. Kempter et al. / Tetrahedron 72 (2016) 7699e7714

1. MeO OMe O

MeO

O

HO

OTBDMS

TsOH H O

OMe 2. LiAlH / THF 4

OH

dimethyl (2R,3R)-tatrate

tetraethylammonium salt in DMF yields a MOM-protected O-dienyl thiohydroxamate as 50/50-mixture of stereoisomers. The diastereomers separate on the silica gel column, used for purifying the 3-(3-hydroxynona-1,8-dien-5-yl)thiazolethione 1f after having solvolytically cleaved off the MOM-protecting group (Scheme 8). Only isomer rel-(3R,5S)-1f provided a correct combustion analysis and was therefore considered in the subsequent alkenoxyl radical study.

2

3

O

3. NaH / THF TBDMSCl

H

OH

threo-8 (53%) 4. (COCl)2 / DMSO / NEt3 + – 5. Ph3PCH3 Br KOtBu / THF

7. TsCl / DABCO 8. MTTO – NEt +

OMTT AcO

2

6. TBAF / THF OH

4

3

H O

9. PPTS / MeOH

OAc

2

3

O

10. Ac2O / NEt3

H

threo-6 (49%)

threo-1d (60%)

Scheme 6. Synthesis of 3-[2,3-threo-2,3-bis-(acetyloxy)pent-4-en-1-oxy]thiazolethione threo-1d from dimethyl (2R,3R)-tartrate.

2.4. Homolytic bromocyclization

R S

HO H

HO

O

1.–5.

OH OH

H 6.–7.

2 3

4

O

D-ribose

S

N H O H O

H

OMAnTT 2

AcO

3

4

OAc 1e (43%)

9 (15%)

Scheme 7. Synthesis of 2,3,4-arabino-configured 3-(hexenoxy)thiazolethione 1e from D-ribose [R¼4-methoxyphenyl; reagents and conditions e 1. step: acetone, concentrated sulfuric acid (81% yield);47 2. step: iodine, imidazole, triphenylphosphine, toluene/acetonitrile (54% yield);48,49 3. step: palladium on charcoal, hydrogen, ethanol (97% yield); 50,51 4. step: methyl triphenylphosphonium bromide, potassium tert-butoxide, tetrahydrofuran (67% yield); 5. step: 3-hydroxy-4-methyl5-(4-methoxyphenyl)-1,3-thiazole-2(3H)-thione (MAnTTOH), diethyl azodicarboxylate, triphenylphosphine, benzene (54% yield); 6. step: hydrogen chloride, methanol (96% yield); 7. step: acetic anhydride, 4-(N,N-dimethylamino)pyridine, dichloromethane (45% yield)].

providing a crystalline target compound 1e, for purifying the ester in the final step by crystallization.46 2.3.4. O-(3-Hydroxy-5-nona-1,8-dienyl) thiohydroxamate 1f. For preparing the C9-carbon skeleton of dienyl tosylate 10 we added but-3-en-1-yl magnesium bromide to 3-(methoxymethyloxy)pent4-enal and esterified the resulting product, 3-(methoxymethyloxy) nona-1,8-dien-5-ol, with p-toluenesulfonyl chloride. Heating tosylate 10 with 3-hydroxy-4-methyl-1,3-thiazole-2(3H)-thione

H

OTs

1.–2.

5

OMTT

3

O 10

OCH3

2.3.5. Stereochemical analysis. All stereocenters of O-alkenyl thiohydroxamates erythro-1d, threo-1d, and 1e derive from enantiopure natural products. All synthetic manipulations used for transforming the starting materials into the target compounds occurred stereospecifically, as concluded from single sets of resonances in proton- and carbon-13 NMR-spectra (Experimental, Table 1). For unknown reasons, optical rotations recorded for erythro-1d and threo-1d scattered from batch to batch, and in one instance even changed sign. Since stereochemical information obtained by transforming single diastereomers suffice to answer all relevant question associated with the study, we refrained from emphasizing absolute configuration of O-alkenyl thiohydroxamates erythro/threo-1d and 1e hereafter.

OH rel-(3R,5S)-1f (23%)

Scheme 8. Preparing 3-(3-hydroxynona-1,8-dien-5-yl)thiazolethione rel-(3R,5S)-1f from dienyl tosylate 10 (Supplementary data) [reagents and conditions e 1. step: 3-hydroxy-4-methyl-1,3-thiazole-2(3H)-thione tetraethylammonium salt, DMF, 40  C (67% yield); 2. step: hydrogen chloride, methanol, and column chromatography for separating diastereomers {rel-(3R,5S)-1f: 35% yield}].

2.4.1. Parameters for conducting alkenoxyl radical reactions. For studying the chemistry of 4-pentenoxyl radicals Iaef, we adhered to a standardized protocol derived from preceding mechanistic investigations.8,22,24 Operational standards thereby relate to (i) the experimental set-up, (ii) methods for quantifying products, and (iii) structure analysis. (i) Experimental set-up. For securing that yields and selectivity are not flawed by technical details associated with the initiating step, we used photochemical and thermal activation for initiating radical chain reactions. In the following, we assessed yields and product manifolds obtained from O-esters 1a and 1b under both conditions, for deciding which of the methods to use as standard. The most effective way for initiating a radical reaction photochemically started from a 83-millimolar solution of 1a in perdeuterobenzene containing bromotrichloromethane. The solution was irradiated in a RayonetÒ-chamber reactor equipped with twelve 350-nm light bulbs. This set-up gave 2-methylsulfanylthiazole 2 in 59% and bromoethers 3a/11a in 71% yield. For initiating the radical reaction thermally, we heated a likewise prepared solution of 1a in the presence of azobisisobutyronitrile (AIBN) as chemical initiator. The thermal version of the radical reaction gave 88% of bromoethers 3a/11a in total, and co-product 2 in 81% yield. The same trend for providing elevated yields under thermal conditions was seen for reactions between O-acetyl-substituted ester 1b and bromotrichloromethane. For example, heating 1b in a 83-millimolar solution of perdeuterobenzene and bromotrichlormethane gave O-acetyloxybromoethers 3b/11b in 89% combined yield, and 90% of thiazole 2. The photochemical reaction provided 77% of bromocyclization products 3b/11b and 71% of coproduct 2. By comparing yields we finally decided to use the thermal method as standard for conducting alkenoxyl radical bromocyclizations of O-alkenylthio-hydroxamates 1aef. Benzoate 1c, under thermal conditions, gave 95% of thiazole 2 and a combined yield of 94% for brominated ethers 3c/11c. Regarding reaction times, thermally initiated conversions of Oalkenyl esters 1aec took no longer than two hours for completion. Extending reaction times diminishes yields and causes sideproducts to appear. Photoreactions of standardized solutions of esters 1aeb were complete within one hour. In some of the experiments the

I. Kempter et al. / Tetrahedron 72 (2016) 7699e7714

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Table 1 Chemical shifts of oxygen-bound carbons and the inner alkene proton of O-alkenyl thiohydroxamates 1aef (in CDCl3, ambient temperature)

OMTT δ

γ

βγ

AcO

OR 1a–c Entry 1 2 3 4 5 6 7 a

H

OMTT δ

AcO

H

OMAnTT

α βγ

OAc

OMTT

α

δ

OH

OAc

erythro/threo-1d

δ

γ

1e

(±)-1f

1/R

Ca/ppm

Cb/ppm

Cg/ppm

1a/H 1b/Ac 1c/Bz erythro-1d threo-1d 1e ()-1f

73.1 72.0 72.0 72.5 73.8 74.0 84.5

35.1 32.5 32.6 71.2 70.8 72.1 da

68.5 71.1 71.7 73.3 72.0 76.9 71.0

Hd/ppm 5.94 5.85 5.97 5.83 5.90 5.79 5.94

(ddd) (ddd) (ddd) (ddd) (ddd) (ddd) (ddd)

Not assigned; for entire sets of chemical shifts, see the Experimental.

2.4.2. Bromocyclization of monosubstituted O-(4-pentenyl) thiohydroxamates 1aec.

reaction mixture turned in an unpredictable manner yellowish or turbid with some of the starting material still present. Extending the reaction time quantitatively causes substrate 1 to quantitative turn over, however, by also leading to a higher product manifold.22,52

(i) Products. In a larger scale-up experiment, conducted under thermal conditions, 1.12 mmol monosubstituted O-alkenyl thiohydroxamate 1a gave 56% of 2-bromomethyl-tetrahydrofuran-3-ol (3a), 4% of 4-bromotetrahydropyran-3-ol (11a), and 84% of disubstituted thiazole 2 (Table 2, entry 1). Tetrahydrofuran 3a was formed under such conditions as 74/26-mixture of 2,3-cis/transisomers.

(ii) Methods for quantifying products. For obtaining the original stereochemical information from bromocyclization product 3, information on chemoselectivity for the reaction between thiohydroxamate 1 and BrCCl3, and maximum yields of products, we

Table 2 Products formed from O-(4-pentenoxy)thiazolethiones 1aec and bromotrichloromethane

OMTT 3

N

C6H6 / 80 °C

1 2 3 a b

O SCCl3

+

2

O

2

+

3

OR

OR 1a–c Entry

Br

S

BrCCl3 / AIBN

3a–c

4

3

Br

OR 11a–c

1/R

2/%

3/% (cis:trans)a

11/% (cis:trans)b

1a/H 1b/Ac 1c/Bz

84 94 75

3a: 56 (74:26) 3b: 71 (68:32) 3c: 69 (68:32)

11a: 4 (65:35) 11b: 11 (57:43) 11c: 12 (50:50)

Stereodescriptors refer to configuration at carbons C2 and C3. Stereodescriptors refer to configuration at carbons C3 and C4.

injected samples taken directly from solutions of products in perdeuterobenzene into a gas chromatograph equipped with a flame ionization detector and coupled to a mass spectrometer. For cross-checking structural assignments, we analyzed samples from the same mixture by NMR-spectroscopy (proton and carbon13). (iii) Structure analysis. All products described in this article were characterized by high resolution mass spectrometry, combustion analysis, and NMR-spectroscopy for constitution analysis. For assigning relative configuration of bromocyclization products (i.e., 3), we relied on shift differences of carbon-13 resonances between cis/trans-isomers (vide infra). For deducing constitution and, wherever possible, relative configuration of brominated tetrahydropyrans, being formed in 13% yield and less (cf. Section 2.5.2), we used mass spectrometry in combination with NMR-spectroscopy. In one instance (for 11a), we independently prepared a bromotetrahydropyran for securing our interpretation.

O-Acetyl-substituted ester 1b yielded 71% of tetrahydrofuran 3b as 68/32-mixture of 2,3-cis/trans-isomers, 11% of tetrahydropyran 11b and 94% of thiazole 2 under standard conditions (Table 2, entry 2). O-Benzoyl-substituted thiohydroxamate 1c provided 69% of disubstituted tetrahydrofuran 3c as 68/32-mixture of 2,3-cis/ trans-isomers, 12% of tetrahydropyran isomer 11c and 75% of thiazole 2, when heated with bromotrichloromethane (Table 2, entry 3). (ii) Stereochemical analysis. For assigning relative configuration of 5-exo-bromocyclization product 3 we relied on a systematic highfield shift of resonances for carbons C2, C3, and for exocyclic bromomethyl carbon C10 in 2,3-cis-isomers. This guideline derives from a combined NMR-spectroscopy/X-ray-diffraction study on diand trisubstituted tetrahydrofurans.8,12 Highfield shifts of resonances in cis-isomers arise from steric deshielding of interacting nuclei (Table 3).53

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Table 3 Carbon-13 NMR-chemical shifts for cis/trans-isomers of 2,3-substituted tetrahydrofurans 3aec (in CDCl3, ambient temperature)

O 3

H

Br O

1'

2

3

H OR

1 2 3 4 5 6

Br 1'

2

H OR

(±)-trans-3a–c

(±)-cis-3a–c Entry

H

3/R

C2/ppm

C3/ppm

C10 /ppm

cis-3a/H cis-3b/Ac cis-3c/Bz trans-3a/H trans-3b/Ac trans-3c/Bz

82.2 80.8 81.2 85.1 83.2 83.3

71.9 73.7 74.5 75.1 77.4 78.0

29.0 28.4 28.7 32.8 33.1 33.2

(ii) Stereochemical analysis of tetrahydrofurans. According to the stereochemical guideline for interpreting carbon-13 NMR-spectra described in Section 2.4.2, the major stereoisomer formed from Opentenyl ester erythro-1d is the all-cis-configured tetrahydrofuran ciserythro-3d. This guideline in a similar manner allows to assigning spectral data of cisthreo-3d from the equimolar mixture of diastereoisomers (Table 4).

2.4.3. Products from erythro/threo-isomers of 3-[2,3-bis-(acetyloxy) pent-4-enyloxy]-4-methyl-1,3-thiazole-2(3H)-thione 1d. (i) Products. O-(2,3-Bisacetyloxypentenyl) thiohydroxamate erythro-1d furnished 67% of bromoethers erythro-3d and erythro11d taken together, and 49% of disubstituted thiazole 2, when heated in a laboratory microwave to 80  C in a solution of a,a,atrifluorotoluene under otherwise standard conditions (Scheme 9, top).

OMTT AcO

3 2

OAc erythro-1d

2.4.4. Products from 3-[arabino-3,4-bis-(acetyloxy)hex-5-enoxy]1,3-thiazole-2(3H)-thione 1e. (i) Products. Arabino-configured O-(3,4-bisacetyloxyhexenyl) thiohydroxamate 1e reacted with bromotrichloromethane in boiling benzene containing AIBN to give 50% bromomethyltetrahydrofuran 3e, and 10% of bromotetrahydropyran 11e, and 55% of trisubstituted thiazole 12 (Scheme 10). Chromatography on silica gel allows to separate tetrahydropyran 4,5-trans-11e from

S

BrCCl3 / AIBN MW / 80 °C C6H5CF3

spectrometer, having one proton chelated by two vicinal acetyloxy groups. Heating stereoisomer threo-1d in a solution of a,a,a-trifluorotoluene (80  C) containing bromotrichloromethane and AIBN gave 65% of thiazole 2, and a combined yield of 51% for bromocyclization products threo-3d and threo-11d (Scheme 9, bottom). For assigning constitution and configuration, we, again, relied on information gained from analyzing sets of threo-3d/ 11d-mixtures containing differing isomer ratios.

SCCl3

N

H

O +

H AcO

Br

2

4

3

H OAc

O + AcO

4

5

Br

OR

erythro-3d (54%)

2 (49%)

3

erythro-11d (13%)

2,3-cis:trans = 70:30 4,5-cis:trans = 69:31

OMTT AcO

2

3

OAc threo-1d

S

BrCCl3 / AIBN MW / 80 °C C6H5CF3

N 2 (65%)

H

O SCCl3

+

H AcO

4

Br

2 3

H OAc

threo-3d (44%)

O + AcO

3

4

5

Br

OR threo-11d (7%)

2,3-cis:trans = 50:50 4,5-cis:trans = 71:29 Scheme 9. Products formed from radical reactions between bromotrichloromethane and 3-[erythro-2,3-bis-(acetyloxy)pent-4-enoxy]thiazolethione erythro-1d [top; yields for experiment conducted via photochemical activation (l¼350 nm, 22  C, 30 min) on a 196-millimolar scale of 1d in C6D6 containing 9.6 equivalents of BrCCl3: 77% of 2, 68% of erythro3d and erythro-11d taken together] and stereoisomer threo-1d [bottom; yields for experiment conducted via photochemical activation (l¼350 nm, 22  C, 30 min) on a 196millimolar scale of 1d in C6D6, containing 9.0 equivalents of BrCCl3: 53% of 2, 72% of threo-3d and threo-11d taken together]; MW¼microwave.

All attempts to chromatographically separate 2,3-cis/transisomers of bromoethers 3d and 11d gave in our hands product mixtures in differing ratios. Superimposing information gained from such mixtures allowed to characterize all products by chemical shifts and fine structures of proton resonances. In high resolution mass spectrometra bisacetates erythro-3d/11d showed the peculiar phenomenon of being by one proton heavier than calculated for the molecular formula C9H13O5Br. This excess mass-per-charge unit is retained throughout the fragmentation of erythro-3d/11d, until one of the acetyl groups dissociates off. Given consistent proton integrals and fine structures in underlying NMR-spectra, we assigned molecular ions C9H14O5Brþ to derivatives of erythro-3d/11d, generated in the mass

all-cis-configured tetrahydropyran 4,5-cis-11e, and a 2,3-cis/transmixture of bromomethyltetrahydrofuran 3e. (ii) Stereochemical analysis. From low field-shifted resonances of carbons C2eC4 and carbon C10 we concluded that the major 5-exobromocyclization product obtained from arabino-configured Ohexenoxyl radical Ie is the 2,3-trans-stereoisomer of tetrahydrofuran 3e (Table 5). 2.4.5. Products from 3-[rel-(3R,5S)-3-hydroxynona-1,8-dien-5-oxy]4-methyl-1,3-thiazole-2(3H)-thione 1f. (i) Products. Heating or photolyzing O-nonadienyl thiohydroxamate 1f in benzene/bromotrichloromethane-solutions

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7705

Table 4 Selected carbon-13 NMR-chemical shifts of 3,4-bisacetyloxy-2-bromomethyl-tetrahydrofurans erythro/threo-3d (in C6D6, ambient temperature)

H

O 4

H AcO

Br

2 3

H OAc

H AcO

ciserythro-3d

4

Br

2

H OAc

3

H

O

1'

H AcO

cisthreo-3d

4

Br

2 3

H

O

1'

H OAc

H AcO

transerythro-3d

4

Br 1'

2 3

H OAc

transthreo-3d

3d

C2/ppm

C3/ppm

C4/ppm

C10 /ppm

ciserythro cisthreo transerythro transthreo

79.2 80.2 79.6 83.9

71.9 76.4 74.5 80.2

72.2 77.9 72.3 78.4

29.2 28.0 33.3 32.2

Entry 1 2 3 4

H

O

1'

H AcO 2

An OMAnTT BrCCl3 / AIBN 3

C6H6 / 80 °C

OAc 1e

H

S SCCl3 +

N

H AcO

12 (55%)

H

O 4

Br

2 3

H

O

+

H OAc

4

AcO 3

5

Br

OAc 11e (10%)

3e (50%)

2,3-cis:trans = 30:70 4,5-cis:trans = 20:80 Scheme 10. Products formed from 3-[arabino-3,4-bis-(acetyloxy)hex-5-enoxy]-1,3-thiazole-2(3H)-thione 1e and bromotrichloromethane.

Table 5 Proton and carbon-13 chemical shift values used for distinguishing tetrasubstituted tetrahydrofuran cis-3e from isomer trans-3e (CDCl3, ambient temperature)

H H AcO

Br H 1'

O 4

H

2 3

H OAc

H AcO

cis-3e Entry 1 2

Br H 1'

O 4

into 2-methylthiazole-2(3H)-thione and yet unidentified organotin derivatives when being contacted with silica gel, and therefore was characterized and quantified from the reaction mixture by protonNMR spectroscopy.24 2,5-Substituted tetrahydrofuran 15 formed from O-nonadienyl ester 1f and tributylstannane as 27/73-mixture of cis/trans-isomers, which we used for stereochemical analysis. Based on a model developed from theory for predicting selectivity in 5-exo-cyclization of monosubstituted 4-pentenoxyl radicals, we think that the major stereoisomer is disubstituted tetrahydrofuran trans-15.1 Since most resonances of cis/trans-15 overlap, we unfortunately could not conduct a more sophisticated stereochemical analysis at this point. From the reaction mixture we furthermore separated trisubstituted tetrahydrofuran 14 as 20/80-mixture of 2,3-cis/transisomers in a total yield of 20%. This mixture, however, was contaminated by 13 percent by weight with a third product, showing in high resolution mass spectra identical molecular masses to tetrahydrofurans 14 and 15. From supplementary NMR-spectroscopic information we concluded that the third product is a tetrahydropyran formed from 6-endo-cyclization. Since the yield of the product was rather low (3%), we were not able to provide at this point a complete structure analysis (see also Section 2.5.2). Given the propensity of hydroxyl-substituted alkoxyl radicals to afford a higher fraction of 6endo-cyclized products, we propose that the third product arises from 6-endo-addition of If to the allylic alcohol segment.

2 3

H OAc

trans-3e

3

C2/ppm

C3/ppm

C4/ppm

C10 /ppm

cis-3e trans-3e

77.9 78.1

72.9 74.9

72.4 73.6

29.4 33.7

gives products of sequential alkoxyl radical cyclization and bromotrichloromethane addition across the remaining carbon-carbon double bond.52,54 For preventing such side reactions to occur, we changed the mediator from bromotrichloromethane to tributylstannane. This modification, in all instances studied so far, never changed stereo- and regioselectivity of alkenoxyl radical additions.1,8 Boiling a solution of O-nonadienyl ester 1f in benzene in the presence of a 3.7-fold excess of tributylstannane, provided a 26/74mixture of tetrahydrofurans 14 and 15 in a total yield of 76%, besides 79% of thiazole 13 (Scheme 11). Tin compound 13 fragments

H

OMTT

Bu3SnH AIBN C6H6 / 80 °C

OH rel-(3R,5S)-1f

H

S N

SSnBu3 +

13 (79%)

H

H

O 2 3

H OH

+

O 5

HO H 2

14 (20%)

15 (56%)

dr = 20:80

dr = 27:73

Scheme 11. Products formed from 3-[rel-(3R,5S)-3-hydroxynona-1,8-dien-5-oxy]-4-methyl-1,3-thiazole-2(3H)-thione 1f and tributylstannane.

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(ii) Analyzing regioselectivity in 5-exo-cyclization. From a doublet of double-doublet fine structure for the inner alkene proton and larger shift dispersion for the two terminal protons, we concluded that the major cyclization product obtained from nonadien-5-yl ester 1f is disubstituted tetrahydrofuran 15 (Fig. 4, top and bottom). In tetrahydrofuranol 14, the resonance of the inner alkene proton is split into a triplet of double-doublet and the terminal protons are less shift-dispersed (Fig. 4, center).

H• CH2

O

k–1 cis

H OAc

H Br

O

H OAc

trans-IIb kBr trans

BrCCl3

H • CH2

O

H Br H OAc

H OAc IIb

cis-3b

H • CH2 H OAc

k1cis/trans

BrCCl3 O

O

OAc Ib

cis-IIb kBr cis

k–1 trans

O•

trans-3b

cis:trans ≈ 70:30

d [3b] dt life-time for IIb: τ

= kBr [BrCCl3][IIb] =

(eq. 1)

1

(eq. 2)

Br

k [BrCCl3] kBr cis

=

kBr trans

(app. 1)

Scheme 12. Scheme of elementary reactions, kinetic equations (eqs. 1e2) and approximation (app. 1) set up for identifying thermochemical contributions to 2,3-cisselectivity in 5-exo-cyclization of 3-acetyloxypentenoxyl radical Ib (see also text).

Fig. 4. Section of proton NMR-spectra displaying resonances of inner and terminal alkene protons of tetrahydrofurans 14 and 15, and O-[rel-(3R,5S)-3-hydroxynona-1,8dien-5-yl] thiohydroxamate 1f for comparison.

2.5. Mechanistic and stereochemical aspects To find out what causes 3-substitued-4-pentenoxyl radicals Iaec to cyclize 2,3-cis-selectively, we at first verified that the intramolecular addition follows kinetic control. For this purpose, we monitored stereochemical integrity of diastereomerically pure cyclized radicals cis-IIb and trans-IIb under conditions that extended their life-times by a factor 100. 2.5.1. On reversibility of 3-acyloxypent-4-en-1-oxyl radical 5-exocyclization. (i) Kinetic approach. In a kinetically controlled reaction a notable barrier would prevent tetrahydrofuranyl-2-methyl radical cis-IIb or stereoisomer trans-IIb from ring opening to alkenoxyl radical I in a b-fragmentation. If the oxygen radical formed, a de-novocyclization would become apparent by altering stereochemical integrity of previously pure cis-IIb and trans-IIb towards an equilibrium mixture presumably of 68/32 (Scheme 12 and eq. 1). By extending the life-time of radicals cis-IIb and trans-IIb by, for example, a factor 100 compared to conditions applied in bromocyclization, the stereochemical fingerprint from a possible ringopening should become apparent by stereochemical scrambling. The kinetic life-time of carbon radical IIb in bromocyclization is defined as inverse pseudo-first order rate constant for homolytic substitution for brominative trapping. This rate constant numerically derives from the product between the rate constant kBr and concentration of bromotrichloromethane (eq. 2).55 In bromocyclization starting from a 0.2 molar solution of O-alkyl

thiohydroxamate 1b, as used in the standard operational procedure, the concentration of bromotrichloromethane declines from 1.490.01 M at the beginning towards 0.910.01 M by the end. The rate constant kBr for trapping primary carbon radicals cis-IIb and trans-IIb, is approximately 3.9107 M1s1. This value derives from the experimental rate constant for hept-6-en-2-yl radical-trapping with bromotrichloromethane (kBr¼1.2108 M1s1 at 26  C in benzene) divided by three.56 The factor three corrects for a polar rate effect arising from alkyl substitution at the radical center.57 Since rate effects of b-substituents are in general small, we assumed that kBrcis and kBrtrans are identical (approximation 1).58 Based on these approximations, life-times of cis/trans-IIb in standard bromocyclizations are 1.7108 s at the beginning of the reaction, and 2.8108 s by the end. For experimentally extending tetrahydrofuran-2-methyl radicals life-times, we changed the mediator to tributylstannane. The tin compound traps, primary carbon radicals, for example the 1butyl radical with a rate constant of kH¼2.4106 M1 s1 at 300 Kelvin in benzene, which is 16-times slower than the reaction with bromotrichloromethane (Scheme 13). The ratio kBr/kH remains constant, if activation parameters for the two processes respond

O

H Br H OAc

Bu3Sn • – Bu3SnBr

IIb

Bu3SnH

O

kH

H H OAc

+ Bu3Sn •

16

3b

d [16] dt

= kH [IIb][Bu3SnH]

(eq. 3)

Scheme 13. Elementary reactions (top) and differential equation (bottom) for comparing rates and life-time of alkyl radical trapping under reductive conditions (eq. is short for equation).

I. Kempter et al. / Tetrahedron 72 (2016) 7699e7714

similar to a change in reaction temperature. On the basis of this assumption, we extrapolated that the life-time of primary alkyl radicals cis/trans-IIb in a 0.17 molar solution of tributylstannane, as used for conducting the controls, extends to 2.5106 s. (ii) Stereochemical study. For putting our theoretical considerations on radical life-times into practice, we heated a 0.07 molar solution of 2-bromomethyltetrahydrofuran-3-yl acetate cis-3b in benzene with an excess of tributylstannane (co¼0.17 M). The reduction furnishes diastereomerically pure 2-methyltetrahydrofur anyl acetate cis-16. Stereoisomer trans-3b reacts with tributylstannane under identical conditions to 3-acetyl-2-methylte trahydrofuran trans-16. From gas chromatograms, we concluded that 2-methyltetrahydrofurans cis/trans-16 form in essentially quantitative yield. The amount of products obtained after removing organotin compounds declined to 58e61% (Scheme 14). Since no stereochemical scrambling occurs upon reducing the two diastereomers of 2-bromomethyltetrahydrofuryl acetates 3b we concluded that carbon radicals cis/trans-IIb retain configuration in the environment used for conducting homolytic bromocyclization.

H Br

O

H OAc

H

O

Bu3SnH / AIBN

H OAc

C6H6 / 80 °C

(±)-cis-3b

7707

2,3-cis-selectivity in tetrahydrofuran synthesis have the same origin. For elucidating constitution and configuration of minor cyclization products 11aee, we analyzed fragmentation pattern from electron impact mass spectra and carbon-13 NMR-chemical shift differences. A diagnostic tool for distinguishing a 2bromomethyltetrahydrofuran from a 3-bromotetrahydropyran is the chemical shift of endocyclic ether carbons, which are high field-shifted by 1.7e14.0 ppm for the six-membered ring. For distinguishing cis-from trans-stereoisomers, we translated absolute values of vicinal coupling constants with the aid of the Karplus-relationship into dihedral angles, and assigned substituent positions accordingly to axial and equatorial locations in the chair conformation of tetrahydropyran.59,60 2.5.3. On the origin of 2,3-cis-selective pent-4-en-1-oxyl radical cyclization. (i) Transition structures. In transition structures associated with 5-exo-C,O-cyclization, the radical oxygen, the inner alkene carbon (C5), and the allylic carbon (C4) lie for stereoelectronic reason in a plane. Carbons C2 and C3 are offset into opposite directions from this plane, leading to distorted twist (T)-conformers 2T3 (Fig. 5, left) or 2T3. 2

(±)-cis-16 (58%)

bexo

O• H Br

O

H OAc (±)-trans-3b

(±)-trans-16 (61%)

Scheme 14. Reducing 2-bromomethyltetrahydrofurans cis/trans-3b with tributylstannane (diastereomeric purity of all products >98:2, according to information from GC-MS in combination with proton NMR-spectroscopy; for reactand concentrations, refer to the text).

2.5.2. On 6-endo-cyclization. Bromotetrahydropyrans 11aee are by-products in homolytic bromocyclization of O-alkenyl thiohydroxamates 1aee. From arguments summarized in Section 2.5.1, we expect 6-endo-cyclizations proceed kinetically controlled as well. The experimental tetrahydropyran/tetrahydrofuran-ratio exceeds in most instances the expectation value of 2/98, derived from cyclizations of allylic carbon-substituted 4-pentenoxyl radicals, by a factor 6e7 (Table 6).2 We think that declining regioselectivity and

Table 6 Survey of selectivity data for cyclization of substituted 4-penten-1-oxyl radicals Iaee (80  C)

• CH2

O

R1 R

2

R

5-exo

R1

1 2 3 4 5 6 a b

6-endo 5

2

R

3

6

R1 R

R3 III

I

R1

R2

R3

II:IIIa

2,3-cis:trans-IIb

Ia Ib Ic erythro-Id threo-Id Ie

H H H H H CH3

H H H OAc OAc OAc

OH OAc OBz OAc OAc OAc

94:6 87:13 85:15 81:19 86:14 83:17

74:26 68:32 68:32 70:30 50:50 30:70

Approximated from ratio of bromine atom-trapping. Relative configuration of substituents at alkenoxyl radical carbons C2 and C3.

disfavored

(ii) Preferred sites for placing substituents. 2,3-cis-Cyclization, in the twist-model, proceeds via transition structures having the substituent at carbon C4 located pseudo-axially, forming a plane with the alkene carbons (Fig. 6, left). Rotating the vinyl substituent by 180 causes atoms C2 and C3, for arguments summarized in Fig. 5, to interchange positions with respect to the twist plane. This conformational change causes carbon C2 to flip underneath, and carbon C3 above the twist plane, transforming a 2T3-into a 2T3-conformer. The allylic substituent thereby changes position in the twist-conformer from pseudo-axial to pseudo-equatorial. In pseudo-equatorial orientation, a sterically demanding group at carbon C4, for instance methyl, tert-butyl, or phenyl, experiences less strain from other substituents and the heterocyclic core (Fig. 6, right).2,7

synperiplanar 2

CH •

3

Fig. 5. Twist-model for predicting lowest in energy transition structures of the 4pentenoxyl radical in 5-exo-trig-cyclization, having the terminal vinyl group located in exo-bisectional position (bexo, favored), or endo-bisectional orientation (bendo, disfavored).

O

2

R3 I

II Entry

1

O•

bendo

favored

H OAc

C6H6 / 80 °C

O• 3

H

O

Bu3SnH / AIBN

2

X

pa

O•

3

X

O• 3

favored for X = OH, OAc, OBz

2

pe

anticline

favored for X = CH3, tBu, Ph

Fig. 6. Twist-models for transition structures leading to 2,3-cis- (left; pa¼pseudoaxial) or 2,3-trans-5-exo-cyclized products (right; pe¼pseudo-equatorial) from 4pentenoxyl radicals.

(iii) Theory of reactive conformers. Substituents favoring 2,3-ciscyclization are able to overcompensate repulsion from synperiplanar orientation of the vinyl group and pseudo-axially

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orientation of the substituent. Opponents to steric effects in chemical reactivity are polar effects. Alkoxyl radical additions to carbonecarbon double bonds are fast and exothermic reactions having, according to Hammond’s postulate, transition structures located early on the reaction coordinate. A valid theory for interpreting selectivity based on polar effects in transition structures located early on a reaction coordinate is frontier molecular orbital (FMO)-theory. The major difference between transition structures leading to 2,3-cis- and 2,3-trans-cyclization of a 3-substituted 4-pentenoxyl radical arises from relative orientation between allylic substituent X and the plane of the carbonecarbon double bond, which, in turn, effects the p(C,C)-bond energy. In transition structures associated with 2,3-trans-cyclization the alkene and the allylic oxygen substituent adopt an anticline conformation, allowing p-electrons to delocalize into the s*(C,O)-orbital (for X¼O: Fig. 7, right). In transition structures associated with 2,3-cis-cyclization, the alkene entity is not similarly stabilized and therefore a better electron donor for the singly occupied molecular orbital (SOMO) of the oxygen radical (for X¼O: Fig. 7, left).

the hydroxy and the vinyl group about the s(C2,C3)-bond uncouples p(C,C)/s*(C,O)-electron delocalization, raising the HOMO-energy of but-3-en-2-ol, until the hydroxy group and the alkene align coplanar in the energetic maximum. (iv) 2,3-cis-Directing effect in multiply substituted 4-pentenoxyl radicals. In proposed transition structure TS-ciserythro-Id, the allylic acetyloxy group and the p(C,C)-bond align synperiplanar. The second acetyloxy group adopts an equatorial position, which is the preferred position for steric reasons. Changing orientation of the underlying twist conformation directs both acetyloxy substituents in transition structure TS-transerythro-Id into unfavorable positions e pseudo-equatorial for the allylic group and axial for the substituent at carbon C2 (Fig. 8, top). By favoring intermediate TS-ciserythro-Id the reaction leads to all-cis-configured tetrahydrofuran ciserythro-3d as major product from O-alkenyl thiohydroxamate erythro-1d.

OAc a

OAc pa O•

TS-ciserythro-Id

pe

TS-transerythro-Id

favored

disfavored

X

R

R H

H X

OAc pa O•

synperiplanar

π(C,C)

OAc

pe

OAc e

O•

anticline

not stabilized

OAc a

σ*(C,X)-stabilized

TS-cisthreo-Id

E

OAc

O•

OAc e

TS-transthreo-Id

Fig. 8. Transition structure models for explaining stereoselectivity in 5-exo-trig-cyclization on the basis of cumulative polar and steric substituent effects in 2,3diacetyloxy-4-pentenoxyl radicals erythro-Id and threo-Id (a¼axial, pa¼pseudo-axial, pe¼pseudo-equatorial, e¼equatorial).

LUMO LUMO HOMO

SOMO HOMO R H X

more π-nucleophilic

X R'O •

R H less π-nucleophilic

Fig. 7. Correlation diagram describing angle dependency of frontier molecular orbital (FMO)-interactions in acceptor-substituted butenes used for explaining the kinetic origin of 2,3-cis-selectivity in oxygen radical additions (R¼e.g., CH3 or CH2CH2O, R0 ¼e.g., primary, secondary, and tertiary alkyl; X¼e.g., OH, OAc, OBz).

In a kinetically controlled reaction, differences in transition structure energies translate into free activation energy differences for competing reaction pathways, as expressible in a selectivity parameter, for example, a relative rate constant. From this argument we concluded that the p(C,C)/s*(C,O)-interaction reduces the rate constant for 2,3-trans-cyclization, allowing 2,3-cis-cyclization to become the more effective pathway for 5-exo-cyclization. Experimentally, the rate effect of an allylic hydroxy group becomes apparent in cyclization of the 3-hydroxynona-1,8-dien-5-oxyl radical 1f, which favors addition to the unsubstituted terminal double bond by a factor three. Stabilizing FMO-interactions between an allylic hydroxy group and the alkene have been put forward earlier for explaining anticline conformation of but-3-en-2-ol in the ground state.61 Rotating

In transition structure TS-cisthreo-Id, the allylic acetyloxy group aligns synperiplanar to the p-bond and the second axial. In diastereomorphic transition structure TS-transthreo-Id, the situation for the two acetyloxy groups reverses e being electronically disfavored for the substituent in position 3 and sterically favored for position 2 (Fig. 8, bottom). Polar and steric effects in both of the proposed transition structures seem to counterbalance, offering no obvious preference for either pathway and explaining a 50/50stereoselectivity for homolytic bromocyclization of O-alkenyl thiohydroxamate threo-1d. arabino-Configured 4-pentenoxyl radical Ie cyclizes 2,3-trans-selectively. The methyl substituent becomes the principal stereoinductor, guiding 5-exo-cyclization by steric effects (Fig. 9). Density functional theory predicts the transition structure for 2,5-trans-cyclization of the 5-hexen-2-oxyl radical to be 3 kJ mol1 lower in free activation energy than the transition structure leading to 2,5-cis-cyclization. This value poses an

OAc a OAc

e O•

a OAc pa

pe O•

OAc e

TS-trans-Ie

TS-cis-Ie

favored

disfavored

Fig. 9. Transition structure models for explaining 2,5-trans-selectivity in 5-exo-trigcyclisation of arabino-configured 3,4-bis(acetyloxy)-5-hex-2-oxyl radical Ie (a¼axial, pa¼pseudo-axial, pe¼pseudo-equatorial, e¼equatorial; arcs symbolize steric repulsion between interconnected substituents).

I. Kempter et al. / Tetrahedron 72 (2016) 7699e7714

approximate upper limit for the 2,3-cis-directing effect of the acetyloxy group. 3. Concluding remarks 2,3-cis-Selectivity arises from electrophilicity at oxygen in homolytic addition to non-activated double bonds on one side and a stereoelectronic effect exerted by an allylic hydroxy, acetyloxy or benzoyloxy substituent on the other. This combination kinetically disfavors 2,3-trans-ring closures of 3-acceptor-subsituted 4pentenoxyl radicals, allowing the a 2,3-cis-stereoisomer of a substituted tetrahydrofuran to become principal cyclization product. According to theory, 2,3-cis-selectivity should extend to other acceptor groups X in allylic position and to other electrophilic radicals. The stronger X withdraws p-electrons toward the s*(C,X)orbital, the more pronounced 2,3-cis-stereocontrol shall be. At some point, we expect steric repulsion between the vinyl group and X to counteract the polar 2,3-cis-directing effect. Using WinsteinHolness A-parameters62,63 and electronegativity of atoms, we expect allylic halogens to be potential 2,3-cis-directing substituents. Nitrogen and sulfur groups, on the other hand possibly are borderline cases. Addressing questions of this kind will help to expand our knowledge about polar effects in oxygen radical chemistry and the role such effects play for controlling selectivity in homolytic carboneoxygen bond formation.8,64e66 This is particularly interesting because 2,3-cis-selectivity adds a component to synthesis of tetrahydrofurans in pH-neutral non-oxidative environment, not available so far from carbon substitution. The key for refining the existing reaction model, as far as we understand the mechanism, lies in the interplay between steric and polar substituent effects acting on transition structures. We will report in an upcoming article on this topic. 4. Experimental 4.1. General For general laboratory practice and instrumentation see the Supplementary data. 4.2. 3-Alkenoxythiazole-2(3H)-thiones 4.2.1. General method for hydroxy group O-acetylation. A solution of 3-alkenoxythiazole-2(3H)-thione MTTOR 1b or 1dee (1 equiv), triethylamine (0.5e3.8 equiv), N,N-dimethylaminopyridine (DMAP, 0.1e0.35 equiv) in dichloromethane (6e25 mL/mmol MTTOR) was treated at 0  C with acetic anhydride (2.4e5.0 equiv). The mixture was stirred for 12e22 h at 22  C and treated afterwards with water (7.5 mL/mmol MTTOR). Extracting the reaction mixture with diethyl ether (310 mL/mmol MTTOR) furnishes an organic solution, which was successively washed with water, an aqueous saturated solution of NaHCO3, and brine (je 15 mL/mmol MTTOR). The organic solution was dried (MgSO4) and concentrated under reduced pressure (600 mbar, 40  C) to leave a residue, which was crystallized from the solvent specified below, or purified by chromatography on silica gel (SiO2) as stationary phase. 4.2.2. 3-(3-Hydroxypent-4-en-1-oxy)-4-methylthiazole-2(3H)-thione (1a). A solution of 3-[3-(methoxymethyloxy)pent-4-en-1oxy]-4-methylthiazole-2(3H)-thione (2.51 g, 9.11 mmol; Supplementary data) in methanol (57 mL) was treated with aqueous hydrochloric acid [4.7 mL, 37% (w/w)]. Stirring at 22  C was continued for 3 days and 30 min. Water (60 mL) was afterwards added to furnish a mixture, which was extracted with diethyl ether

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(370 mL). Combined organic extracts were washed with an aqueous saturated solution of NaHCO3 (70 mL) and brine (70 mL). The solution was dried (MgSO4) and the solvent was removed under reduced pressure (600 mbar, 40  C) to afford a residue that was purified by chromatography (diethyl ether). Yield: 1.81 g (7.82 mmol, 86%), pale yellow oil. Rf¼0.36 (diethyl ether). 1H NMR (CDCl3, 400 MHz) d 1.83 (dddd, 1 H, J¼14.8, 9.8, 5.0, 3.7 Hz), 2.07 (dddd, 1 H, J¼14.7, 9.8, 4.4, 3.4 Hz), 2.31 (d, 3 H, J¼1.0 Hz), 3.54 (s, 1 H, OH), 4.39e4.43 (m, 1 H), 4.59e4.64 (m, 2 H), 5.14 (dt, 1 H, Jd¼10.5 Hz, Jt¼1.5 Hz), 5.33 (dt, 1 H, Jd¼17.2 Hz, Jt¼1.6 Hz), 5.94 (ddd, 1 H, J¼17.2, 10.6, 5.5 Hz), 6.21 (d, 1 H, J¼1.5 Hz). 13C NMR (CDCl3, 100 MHz) d 13.3, 35.1, 68.5, 73.1, 103.2, 114.7, 137.8, 139.9, 180.4. Anal. Calcd for C9H13NO2S2 (231.34): C, 46.73; H, 5.66; N, 6.05; S, 27.72; found: C, 46.71; H, 5.76; N, 6.13; S, 27.89. 4.2.3. 3-(3-Acetyloxypent-4-en-1-oxy)-4-methylthiazole-2(3H)-thione (1b). From 3-(3-hydroxypent-4-en-1-oxy)-4-methylthiazole2(3H)-thione (1a) (462 mg, 2.00 mmol), triethylamine (486 mg, 4.80 mmol), N,N-dimethylaminopyridine (DMAP, 24 mg, 0.20 mmol) and acetic anhydride (490 mg, 4.80 mmol) in dichloromethane (12 mL) according to procedure 4.2.1. Yield: 447 mg (1.64 mmol, 82%), colorless crystalline solid, mp 63e64  C (from diethyl ether/pentane). Rf¼0.30 (diethyl ether). 1H NMR (CDCl3, 400 MHz) d 2.09 (s, 3 H, CH3), 2.16e2.22 (m, 2 H), 2.26 (d, 3 H, J¼1.2 Hz), 4.39e4.45 (m, 1 H), 4.48e4.53 (m, 1 H), 5.24 (dt, 1 H, Jd¼10.5 Hz, Jt¼1.1 Hz), 5.33 (dt, 1 H, Jd¼17.2 Hz, Jt¼1.2 Hz), 5.47e5.52 (m, 1 H), 5.85 (ddd, 1 H, J¼17.2, 10.6, 6.3 Hz), 6.15 (d, 1 H, J¼1.0 Hz). 13C NMR (CDCl3, 100 MHz) d 13.4, 21.2, 32.5, 71.1, 72.0, 102.7, 117.6, 135.5, 137.5, 170.1, 180.4. Anal. Calcd for C11H15NO3S2 (273.38): C, 48.33; H, 5.53; N, 5.12; S, 23.46; found: C, 48.39; H, 5.58; N, 5.17; S, 23.38. 4.2.4. 3-(3-Benzoyloxypent-4-en-1-oxy)-4-methylthiazole-2(3H)thione (1c). Pyridine (0.35 mL, 4.30 mmol) was added at room temperature to a solution of 3-(3-hydroxypent-4-en-1-oxy)-4methylthiazole-2(3H)-thione (1a) (500 mg, 2.15 mmol) in dichloromethane (38 mL). The reaction mixture was cooled to 0  C and treated at this temperature in a dropwise manner with benzoyl chloride (604 mg, 4.30 mmol). The resulting mixture was stirred for 20 h at 22  C and treated afterwards with water (20 mL). Extracting the reaction mixture with dichloromethane (320 mL) furnishes an organic solution which was washed with brine (210 mL), dried (MgSO4), and concentrated under reduced pressure (600 mbar, 40  C). The remaining residue was purified by chromatography [SiO2, diethyl ether/pentane¼1:1(v/v)]. Yield: 374 mg (1.11 mmol, 52%), pale yellow oil. Rf¼0.29 [diethyl ether/pentane¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 2.21 (d, 3 H, J¼1.4 Hz), 2.33e2.36 (m, 2 H), 4.42e4.47 (m, 1 H), 4.60e4.65 (m, 1 H), 5.28 (dt, 1 H, Jd¼10.5 Hz, Jt¼1.2 Hz), 5.42 (dt, 1 H, Jd¼17.2 Hz, Jt¼1.3 Hz), 5.75e5.79 (m, 1 H), 5.97 (ddd, 1 H, J¼17.1, 10.7, 6.1 Hz), 6.12 (d, 1 H, J¼1.3 Hz), 7.43e7.47 (m, 2 H), 7.56e7.59 (m, 1 H), 8.05e8.07 (m, 2 H). 13C NMR (CDCl3, 100 MHz) d 13.4, 32.6, 71.7, 72.0, 102.7, 117.7, 128.5, 129.6, 130.0, 133.2, 135.5, 137.6, 165.6, 180.4. Anal. Calcd for C16H17NO3S2 (335.44): C, 57.29; H, 5.11; N, 4.18; S, 19.12; found: C, 57.21; H, 5.22; N, 4.05; S, 19.05. 4 . 2 . 5 . 3 - [ ( 2 R , 3 S ) - 2 , 3 - B i s ( a c e t yl o x y ) -p en t - 4 - e n - 1 - o x y ] - 4 methylthiazole-2(3H)-thione erythro-(1d). A solution of 3-[(2R,3S)isopropylidendioxypent-4-en-1-oxy]-4-methylthiazole-2(3H)-thione erythro-(7) (980 mg, 3.41 mmol) in methanol (70 mL) was treated with aqueous hydrochloric acid [2.76 mL, 37% (w/w)]. The reaction mixture was stirred for 8 h at 22  C. Diethyl ether (20 mL) was added and the mixture was extracted with diethyl ether/petroleum ether¼2:1 (v/v) (330 mL). Combined organic solutions were concentrated under reduced pressure (370 mbar, 40  C) to leave 3-[(2R,3S)-dihydroxypent-4-en-1-oxy]-4-methylthiazole-

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2(3H)-thione as product, which was used as obtained in the succeeding step. Yield: 669 mg (2.73 mmol, 80%), colorless oil. 1H NMR (CDCl3, 600 MHz) d 2.32 (d, 3 H, J¼1.2 Hz), 3.06 (br s, 1 H), 3.94 (d, 1 H, J¼1.2 Hz), 4.05 (br s, 1 H), 4.33 (br s, 1 H), 4.36 (dd, 1 H, J¼9.4, 6.8 Hz), 4.49 (dd, 1 H, J¼9.4, 3.8 Hz), 5.28 (d, 1 H, J¼10.6 Hz), 5.38e5.45 (m, 1 H), 5.95 (ddd, 1 H, J¼17.0, 10.8, 5.7 Hz), 6.23 (d, 1 H, J¼1.2 Hz). 13C NMR (CDCl3, 100 MHz) d 13.3, 71.7, 72.9, 78.7, 103.4, 117.3, 136.1, 138.0, 180.6. 3-[(2R,3S)-2,3-dihydroxypent-4-en-1oxy]-4-methylthiazole-2(3H)-thione (524 mg, 2.12 mmol), triethylamine (818 mg, 8.08 mmol, 1.12 mL), N,N-dimethylaminopyridine (DMAP, 26.0 mg, 0.21 mmol) and acetic anhydride (821 mg, 8.04 mmol, 0.76 mL) were dissolved in dichloromethane (50 mL) according to general procedure 4.2.1. Eluent used for chromatographic purification: ethyl acetate/pentane¼2:1 (v/v). Yield: 655 mg (1.98 mmol, 93%), yellow oil. Rf¼0.40 [petroleum ether/ diethyl ether¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 2.10 (s, 3 H), 2.11 (s, 3 H), 2.24 (d, 3 H, J¼1.2 Hz), 4.46 (dd, 1 H, J¼9.6, 7.0 Hz), 4.78 (dd, 1 H, J¼9.6, 2.5 Hz), 5.33e5.42 (m, 3 H), 5.57 (ddt, 1 H, Jd¼6.1, 4.8 Hz, Jt¼1.2 Hz), 5.83 (ddd, 1 H, J¼17.1, 10.6, 6.4 Hz), 6.15 (d, 1 H, J¼1.2 Hz). 13C NMR (CDCl3, 100 MHz) d 13.2, 20.9, 21.0, 71.2, 72.5, 73.3, 102.7, 120.1, 131.3, 137.3, 169.6, 170.0, 180.4. Anal. Calcd for C13H17NO5S2 (331.41): C, 47.11; H, 5.17; N, 4.23; S, 19.35; found: C, 47.02; H, 5.21; N, 4.28; S 19.53. 4.2.6. 3-[(2S,3S)-Bis(acetyloxy)pent-4-en-1-oxy]-4-methylthiazole2(3H)-thione threo-(1d). Pyridinium p-toluenesulfonate (434 mg, 1.73 mmol) was added to a solution of 3-[(2R,3R)-isopropylidenedioxypent-4-en-1-oxy]-4-methylthiazole-2(3H)-thione (451 mg, 1.57 mmol; Supplementary data) in methanol (20 mL) to furnish a solution which was boiled under reflux for 2 days and 2 h. Adding water (20 mL) at room temperature to the mixture affords a suspension, which was extracted with dichloromethane (350 mL). Combined organic solutions were concentrated under reduced pressure (370 mbar, 40  C) to leave 3-[(2S,3S)-dihydroxypent-4-en-1-oxy]-4-methylthiazole-2(3H)thione as crude product, which was used as obtained in the succeeding step. 1H NMR (CDCl3, 600 MHz) d 2.32 (d, 3 H, J¼1.2 Hz), 3.06 (br s, 1 H), 3.91e3.98 (m, 1 H), 4.05 (br s, 1 H), 4.31e4.39 (m, 2 H), 4.49 (dd, 1 H, J¼9.4, 3.8 Hz), 5.28 (d, 1 H, J¼10.6 Hz), 5.38e5.44 (m, 1 H), 5.95 (ddd, 1 H, J¼17.0, 10.8, 5.7 Hz), 6.23 (d, 1 H, J¼1.2 Hz). 13C NMR (CDCl3, 150 MHz) d 13.3, 71.2, 72.3, 79.0, 103.4, 117.5, 136.5, 137.9, 180.6. Crude 3-[(2S,3S)dihydroxypent-4-en-1-oxy]-4-methylthiazole-2(3H)-thione (477 mg), triethylamine (730 mg, 7.21 mmol, 1 mL), N,N-dimethylaminopyridine (DMAP, 22.0 mg, 0.18 mmol) and acetic anhydride (735 mg, 7.19 mmol, 0.68 mL) were dissolved in dichloromethane (50 mL) and treated as described in general procedure 4.2.1, to leave a crude product, which was purified by chromatography using ethyl acetate/pentane¼2:1 (v/v) as eluent. Yield: 431 mg (1.30 mmol, 83% for both steps), yellow oil. Rf¼0.21 [petroleum ether/diethyl ether¼1:1 (v/v)]. 1H NMR (C6D6, 600 MHz) d 1.52 (d, 3 H, J¼1.2 Hz), 1.68 (s, 3 H), 1.76 (s, 3 H), 4.27 (dd, 1 H, J¼9.1, 6.2 Hz), 4.41 (dd, 1 H, J¼9.1, 2.6 Hz), 5.05e5.09 (m, 1 H), 5.12 (d, 1 H, J¼1.2 Hz), 5.27 (dt, 1 H, Jd¼17.2 Hz, Jt¼1.2 Hz), 5.41 (td, 1 H, Jt¼5.9 Hz, Jd¼3.4 Hz), 5.67e5.70 (m, 1 H), 5.78 (ddd, 1 H, J¼17.0, 10.7, 6.0 Hz). 13C NMR (C6D6, 150 MHz) d 13.1, 20.77, 20.79, 71.5, 72.5, 74.0, 102.2, 119.7, 132.6, 137.5, 169.3, 169.8, 181.0. Anal. Calcd for C13H17NO5S2 (331.41): C, 47.11; H, 5.17; N, 4.23; S, 19.35; found: C, 46.95; H, 5.19; N, 4.02; S 18.68. 4.2.7. 3-[(2S,3S,4S)-3,4-O-Bis(acetyloxy)hex-5-en-2-oxy]-4-methyl5-(p-methoxyphenyl)thiazole-2(3H)-thione (1e). From 3[(2S,3S,4S)-3,4-O-bishydroxyhex-5-en-2-oxy]-4-methyl-5-(pmethoxyphenyl)thiazole-2(3H)-thione (880 mg, 2.39 mmol; Supplementary data), triethylamine (121 mg, 1.19 mmol, 167 mL), N,N-dimethylaminopyridine (DMAP, 35.0 mg, 287 mmol) and acetic

anhydride (1.22 g, 12.0 mmol) in dichloromethane (28 mL) according to general procedure 4.2.1. Eluent used for chromatographic purification: diethyl ether/pentane¼1:1 (v/v). Yield: 480 mg (1.06 mmol, 45%), colorless solid. Rf¼0.16 [diethyl ether/ pentane¼1:1 (v/v)]. [a]D 25¼35.0 (c¼1.93 g/100 mL dichloromethane). 1H NMR (CDCl3, 600 MHz) d 1.22 (d, 3 H, J¼6.4 Hz), 2.08 (s, 3 H), 2.09 (s, 3 H), 2.26 (s, 3 H), 3.80 (s, 3 H), 5.26 (dd, 2 H, J¼4.1, 11.1 Hz), 5.30 (d, 1 H, J¼10.5 Hz), 5.38 (d, 1 H, J¼17.4 Hz), 5.53 (t, 1 H, J¼7.3 Hz), 5.79 (ddd, 1 H, J¼17.4, 10.2, 7.6 Hz), 5.93e5.98 (m, 1 H), 6.95 (d, 2 H, J¼8.6 Hz), 7.24 (d, 2 H, J¼8.5 Hz). 13C NMR (CDCl3, 150 MHz) d 12.6, 14.5, 20.9, 21.5, 55.5, 72.1, 74.0, 76.9, 114.7, 119.4, 120.9, 122.6, 129.9, 132.4, 133.5, 160.0, 169.8, 170.2, 178.9. Anal. Calcd for C21H25NO6S2 (451.55): C, 55.86; H, 5.58; N, 3.10; found: C, 56.06; H, 5.70; N, 3.03. 4.2.8. 3-(3-Hydroxynona-1,8-dien-5-oxy)-4-methylthiazole-2(3H)thione (1f). A solution of 3-[3-(methoxymethyloxy)nona-1,8-dien5-oxy]-4-methylthiazole-2(3H)-thione (1.36 g, 4.12 mmol; Supplementary data) in methanol (27 mL) was treated with aqueous hydrochloric acid [37% (w/w), 0.92 mL, 9.45 mmol]. The reaction mixture was allowed to stir for 18 h at 22  C. Adding water (20 mL) and diethyl ether (20 mL) provided a two-phase system. The aqueous layer was extracted with diethyl ether (310 mL). Organic washings were combined with the organic layer from the reaction mixture and washed with an aqueous saturated solution of NaHCO3 (30 mL) and brine (30 mL). After drying (MgSO4), the organic solvent was removed under reduced pressure (600 mbar, 30  C) to leave a residue, which was purified by chromatography [diethyl ether/pentane¼1:2 (v/v)]. rel-(3S,5S)-3-(3-Hydroxynona1,8-dien-5-oxy)-4-methylthiazole-2(3H)-thione. Yield: 457 mg (1.60 mmol, 39%), pale yellow liquid. Rf¼0.35 [diethyl ether/ pentane¼1:2 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.63e1.75 (m, 2 H), 1.78e1.84 (m, 2 H), 1.94e2.14 (m, 2 H), 2.27 (d, 3 H, J¼1.1 Hz), 4.71e4.77 (m, 1 H), 4.98e5.03 (m, 2 H), 5.14 (dt, 1 H, Jd¼10.5 Hz, Jt¼1.5 Hz), 5.34 (dt, 1 H, Jd¼17.2 Hz, Jt¼1.6 Hz), 5.40e5.47 (m, 1 H), 5.74 (ddt, 1 H, Jd¼16.9, 10.4 Hz, Jt¼6.5 Hz), 5.93 (ddd, 1 H, J¼17.2, 10.5, 5.3 Hz), 6.26 (d, 1 H, J¼1.1 Hz). 13C NMR (CDCl3, 100 MHz) d 14.2, 29.2, 32.2, 40.4, 67.0, 81.3, 103.6, 114.3, 115.7, 136.7, 139.4, 139.9, 180.9. rel-(3R,5S)-3-(3-Hydroxynona-1,8-dien-5-oxy)-4methylthiazole-2(3H)-thione (1f). Yield: 418 mg (1.46 mmol, 35%), pale yellow liquid. Rf¼0.16 [diethyl ether/pentane¼1:2 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.67e1.73 (m, 2 H), 1.84e1.92 (m, 2 H), 2.02e2.20 (m, 2 H), 2.25 (d, 3 H, J¼1.3 Hz), 4.56e4.60 (m, 1 H), 4.98e5.04 (m, 2 H), 5.13 (dt, 1 H, Jd¼10.5 Hz, Jt¼1.4 Hz), 5.33 (dt, 1 H, Jd¼17.2 Hz, Jt¼1.5 Hz), 5.45e5.51 (m, 1 H), 5.76 (ddt, 1 H, Jd¼17.0, 10.4 Hz, Jt¼6.5 Hz), 5.94 (ddd, 1 H, J¼17.2, 10.5, 5.5 Hz), 6.22 (d, 1 H, J¼1.3 Hz). 13C NMR (CDCl3, 100 MHz) d 14.1, 29.1, 32.1, 39.9, 71.0, 84.5, 103.3, 114.7, 115.6, 136.8, 139.2, 140.0, 180.8. Anal. Calcd for C13H21NO2S2 (285.43): C, 54.70; H, 6.71; N, 4.91; S, 22.47; found: C, 54.57; H, 6.92; N, 4.91; S, 22.19. 4.3. Radical bromocyclizations 4.3.1. General method for thermally initiated radical reactions. Azobisisobutyronitrile (AIBN) (0.25 equiv) was added to a solution of N-(alkenoxy)-4-methylthiazole-2(3H)-thione 1aee (1 equiv) in benzene (5e10 mL/mmol MTTOR) and bromotrichloromethane (8e10 equiv). The mixture is heated under reflux for 1e2.5 h. The solution is allowed to cool to 22  C and concentrated under reduced pressure (200 mbar, 40  C). The residual oil is purified by chromatography using silica gel (SiO2) as stationary phase. 4.3.2. General method for thermally initiated radical reaction in a laboratory microwave. A solution of N-(alkenoxy)-4methylthiazole-2(3H)-thione 1d (1 equiv) and bromotrichloromethane (8.6e9.25 equiv) in a,a,a-trifluorotoluene (3 mL/mmol

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MTTOR) was treated with AIBN (0.25 equiv) and heated for 30 min at 80  C in a laboratory microwave (see Supplementary data). The reaction mixture is allowed to cool to room temperature and concentrated under reduced pressure (70 mbar, 40  C). The remaining residue is purified by chromatography [pentane/diethyl ether¼1:2 (v/v)]. 4.3.3. Conversion of 3-(3-hydroxypent-4-en-1-oxy)-4methylthiazole-2(3H)-thione (1a). Reactants: MTTOR 1a (260 mg, 1.12 mmol), bromotrichloromethane (1.78 g, 0.89 mL, 9.00 mmol), and AIBN (46.0 mg, 0.28 mmol) in benzene (6.1 mL) according to procedure 4.3.1. Reaction time: 2 h. Eluent used for chromatographic purification: diethyl ether/pentane¼1:1 (v/v). 4-Methyl-2(trichloromethylsulfanyl)thiazole (2). Yield: 234 mg (0.94 mmol, 84%), yellow oil. Rf¼0.60 [diethyl ether/pentane¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 2.59 (s, 3 H), 7.33 (s, 1 H). 13C NMR (CDCl3, 100 MHz) d 17.2, 96.8, 122.6, 153.5, 155.6.40 3-Bromotetrahydropyran-4-ol (11a). Yield: 7.1 mg (39.3 mmol, 3.5%, cis:trans ¼ 65:35) isolated as a mixture of tetrahydropyranol 11a and tetrahydrofuranol cis-3a (11a/3a¼8/92), yellow oil. Rf¼0.19 [diethyl ether/pentane¼1:1 (v/v)]. cis-(11a): 1H NMR (CDCl3, 400 MHz) d 1.92e2.06 (m, 2 H), 3.62 (dt, 1 H, Jd¼11.5 Hz, Jt¼4.7 Hz), 3.79 (dd, 1 H, J¼11.8, 3.8 Hz), 3.83e3.96 (m, 3 H), 4.35 (dt, 1 H, Jd¼8.3 Hz, Jt¼3.4 Hz). Retention time (tr)¼11.40 min (for GC/MS conditions see Supplementary data): MS (EI) m/z 121 (35), 108 (44), 101 (26), 100 (70), 83 (100), 73 (59), 55 (37). HRMS (EIþ) m/z 179.9775/ 181.9759 [Mþ]; calculated mass for C5H9O2Brþ: 179.9786/ 181.9765. trans-(11a): tr¼11.28 min: 122 (37), 108 (49), 106 (51), 101 (38), 83 (79), 73 (100), 57 (32). HRMS (EIþ) m/z 181.9772/ 179.9778 [Mþ]; calculated mass for C5H9O2Brþ: 181.9765/ 179.9786. rel-(2S,3R)-2-Bromomethyltetrahydrofuran-3-ol cis-(3a). Yield: 81.9 mg (0.45 mmol, 40%), yellow oil. Rf¼0.16 [diethyl ether/ pentane¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.85 (br s, 1 H, OH), 2.02 (dddd, 1 H, J¼13.4, 6.9, 3.7, 1.4 Hz), 2.16e2.25 (m, 1 H), 3.47e3.55 (m, 2 H), 3.92 (td, 1 H, Jt¼8.6 Hz, Jd¼3.6 Hz), 4.01 (ddd, 1 H, J¼8.3, 6.1, 3.5 Hz), 4.09 (td, 1 H, Jt¼8.7 Hz, Jd¼7.0 Hz), 4.50 (td, 1 H, Jt¼4.3 Hz, Jd¼1.4 Hz). 13C NMR (CDCl3, 100 MHz) d 29.0, 35.4, 67.2, 71.9, 82.2. HRMS (EIþ) m/z 181.9772/179.9778 [Mþ]; calculated mass for C5H9O2Brþ: 181.9765/179.9786; m/z 87.0443 [MþCH2Br]; calculated mass for C4H7Oþ 2 : 87.0446. From a 92:8mixture of tetrahydrofuranol cis-3a and tetrahydropyranol 11a: Anal. Calcd for C5H9O2Br (181.03): C, 33.17; H, 5.01; found: C, 33.22; H, 5.07. 2-Bromomethyltetrahydrofuran-3-ol (3a). Yield (determined vs para-bromobenzaldehyde as internal NMRstandard): 17.3 mg (95.7 mmol, 9%, cis:trans¼15:85), yellow oil. Rf¼0.14 [diethyl ether/pentane¼1:1 (v/v)]. cis-3a: NMR data agreed with values from an authentic sample. trans-3a: 1H NMR (CDCl3, 400 MHz) d 1.76 (br s, 1 H, OH), 1.94 (dddd, 1 H, J¼13.2, 6.3, 4.2, 3.2 Hz), 2.14e2.23 (m, 1 H), 3.32 (dd, 1 H, J¼10.4, 7.3 Hz), 3.45 (dd, 1 H, J¼10.5, 4.8 Hz), 3.96e4.03 (m, 3 H), 4.36 (dt, 1 H, Jd¼6.3 Hz, Jt¼3.1 Hz). 13C NMR (CDCl3, 100 MHz) d 32.8, 34.9, 67.5, 75.1, 85.1. HRMS (EIþ) m/z 87.0447 [MþCH2Br]; calculated mass for C4H7Oþ 2 : 87.0446. rel-(2R,3R)-2-Bromomethyltetrahydrofuran3-ol trans-(3a). Yield (determined vs para-bromobenzaldehyde as internal NMR-standard): 13.8 mg (76.0 mmol, 7%), yellow oil. Rf¼0.11 [diethyl ether/pentane¼1:1 (v/v)]. NMR data agreed with values from an authentic sample. 4 . 3 . 4 . C o nve r s i o n o f 3 - ( 3 - a c e t yl o x y p e n t - 4 - e n - 1 - o x y ) - 4 methylthiazole-2(3H)-thione (1b). Reactants: MTTOR 1b (334 mg, 1.22 mmol), bromotrichloromethane (1.94 g, 0.96 mL, 9.76 mmol), AIBN (51.0 mg, 0.31 mmol) in benzene (6.8 mL) according to procedure 4.3.1. Reaction time: 2 h. Eluent used for chromatographic purification: diethyl ether/pentane¼1:1 (v/v). 4-Methyl-2-(trichloromethylsulfanyl)thiazole (2). Yield (determined vs pentachlorobenzene as internal NMR-standard):

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250 mg (1.15 mmol, 94%), yellow oil. Rf¼0.61 [diethyl ether/ pentane¼1:1 (v/v)]. NMR data agreed with values from an authentic sample. rel-(3R,4R)-3-Bromotetrahydropyran-4-yl acetate trans-(11b). Yield (determined vs pentachlorobenzene as internal NMR-standard): 12.4 mg (55.5 mmol, 4.5%), orange oil. Rf¼0.51 [diethyl ether/pentane¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.68e1.75 (m, 1 H), 2.11 (s, 3 H), 2.19 (ddt, 1 H, Jd¼13.2, 5.0 Hz, Jt¼2.6 Hz), 3.52e3.58 (m, 2 H), 3.90e4.01 (m, 2 H), 4.15 (dd, 1 H, J¼12.0, 4.3 Hz), 4.98 (td, 1 H, Jt¼9.8 Hz, Jd¼4.8 Hz). 13C NMR (CDCl3, 100 MHz) d 21.0, 32.6, 47.8, 66.0, 71.3, 73.7, 170.0. HRMS (EIþ) m/z 143.0711 [MþBr]; calculated mass for C7H11Oþ 3: 143.0708. 2-Bromomethyltetrahydrofuran-3-yl acetate (3b). Yield (determined vs pentachlorobenzene as internal NMR-standard): 194 mg (0.87 mmol, 71%, cis:trans¼68:32), yellow oil. Rf¼0.45 [diethyl ether/pentane¼1:1 (v/v)]. cis-3b: 1H NMR (CDCl3, 400 MHz) d 1.94e2.04 (m, 1 H), 2.07 (s, 3 H), 2.18e2.34 (m, 1 H), 3.41e3.55 (m, 2 H), 3.86e3.95 (m, 1 H), 4.00e4.15 (m, 2 H), 5.39 (ddd, 1 H, J¼5.5, 4.0, 1.7 Hz). 13C NMR (CDCl3, 100 MHz) d 20.9, 28.4, 33.5, 66.9, 73.7, 80.8, 170.1. HRMS (EIþ) m/z 223.9880/ 221.9887 [Mþ]; calculated mass for C7H11O3Brþ: 223.9871/ 221.9892. trans-3b: 1H NMR (CDCl3, 400 MHz) d 1.94e2.04 (m, 1 H), 2.05 (s, 3 H), 2.18e2.34 (m, 1 H), 3.41e3.55 (m, 2 H), 3.86e3.95 (m, 1 H), 4.00e4.15 (m, 2 H), 5.09 (dt, 1 H, Jd¼6.7 Hz, Jt¼2.3 Hz). 13C NMR (CDCl3, 100 MHz) d 20.94, 32.6, 33.1, 67.7, 77.4, 83.2, 170.6. HRMS (EIþ) m/z 129.0551 [MþCH2Br]; calculated mass for C6H9Oþ 3 : 129.0552. rel-(3S,4R)-3-Bromotetrahydropyran-4-yl acetate cis-(11b). Yield (determined vs pentachlorobenzene as internal NMR-standard): 15.3 mg (68.4 mmol, 6%), yellow oil. Rf¼0.43 [diethyl ether/pentane¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.85e1.91 (m, 1 H), 1.95e2.00 (m, 1 H), 2.13 (s, 3 H), 3.62e3.68 (m, 1 H), 3.83e3.89 (m, 2 H), 3.94e3.97 (m, 1 H), 4.30e4.33 (m, 1 H), 5.08 (dt, 1 H, Jd¼7.0 Hz, Jt¼3.3 Hz). 13C NMR (CDCl3, 100 MHz) d 20.99, 32.6, 49.1, 64.2, 69.1, 69.3, 170.0. HRMS (EIþ) m/z 223.9885/221.9902 [Mþ]; calculated mass for C7H11O3Brþ: 223.9871/221.9892. 4 . 3 . 5 . C o nve r s i o n o f 3 - ( 3 - b e n z yl o x y p e n t - 4 - e n - 1 - o x y ) - 4 methylthiazole-2(3H)-thione (1c). Reactants: MTTOR 1c (324 mg, 0.97 mmol), bromotrichloromethane (1.54 g, 0.77 mL, 7.76 mmol), AIBN (39.0 mg, 0.24 mmol) in benzene (5.3 mL) according to procedure 4.3.1. Reaction time: 2 h. Eluent used for chromatographic purification: diethyl ether/pentane¼1:2 (v/v). 4-Methyl-2-(trichloromethylsulfanyl)thiazole (2). Yield: 181 mg (0.73 mmol, 75%), yellow oil. Rf¼0.55 [diethyl ether/pentane¼1:2 (v/v)]. NMR data agreed with values from an authentic sample. rel-(2R,3R)-2-Bromomethyltetrahydrofuran-3-yl benzoate trans-(3c) [Yield (determined vs para-bromobenzaldehyde as internal NMR-standard): 54.7 mg (0.21 mmol, 22%)] and rel-(3R,4R)-3-bromotetrahydropyran-4-bezoate trans-(11c) [Yield (determined vs para-bromobenzaldehyde as internal NMR-standard): 16.2 mg (57 mmol, 6%)], yellow oil. Rf¼0.46 [diethyl ether/pentane¼1:2 (v/v)]. rel-(2R,3R)-2bromomethyltetrahydrofuran-3-yl benzoate trans-(3c): 1H NMR (CDCl3, 400 MHz) d 2.14e2.20 (m, 1 H), 2.33e2.41 (m, 1 H), 3.54e3.58 (m, 1 H), 3.61e3.67 (m, 1 H), 3.99e4.07 (m, 1 H), 4.15e4.22 (m, 1 H), 4.26 (td, 1 H, Jt¼5.0 Hz, Jd¼2.5 Hz), 5.38 (dt, 1 H, Jd¼6.6 Hz, Jt¼2.2 Hz), 7.44e7.49 (m, 2 H), 7.57e7.61 (m, 1 H), 8.02e8.09 (m, 2 H). 13C NMR (CDCl3, 100 MHz) d 32.8, 33.2, 68.0, 78.0, 83.3, 128.5, 129.7, 133.3, 166.2. HRMS (EIþ) m/z 286.0042/ 284.0068 [Mþ]; calculated mass for C12H13O3Brþ: 286.0028/ 284.0048. rel-(3R,4R)-3-Bromotetrahydropyran-4-yl benzoate trans(11c): 1H NMR (CDCl3, 400 MHz) d 1.80e1.91 (m, 1 H), 2.33e2.41 (m, 1 H), 3.61e3.67 (m, 2 H), 3.99e4.07 (m, 1 H), 4.09e4.14 (m, 1 H), 4.15e4.22 (m, 1 H), 5.22 (td, 1 H, Jt¼9.6 Hz, Jd¼4.8 Hz), 7.44e7.49 (m, 2 H), 7.57e7.61 (m, 1 H), 8.02e8.09 (m, 2 H). 13C NMR (CDCl3, 100 MHz) d 32.8, 47.7, 66.0, 71.3, 74.3, 128.5, 129.6, 129.7, 133.3, 166.2. HRMS (EIþ) m/z 286.0065/284.0062 [Mþ]; calculated mass

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for C12H13O3Brþ: 286.0028/284.0048. rel-(2S,3R)-2-Bromomethyltetrahydrofuran-3-yl benzoate cis-(3c). Yield: 122 mg (0.46 mmol, 47%), yellow oil. Rf¼0.38 [diethyl ether/pentane¼1:2 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 2.18e2.24 (m, 1 H), 2.43 (dtd, 1 H, Jd¼14.1, 5.5 Hz, Jt¼8.6 Hz), 3.52e3.61 (m, 2 H), 4.01 (td, 1 H, Jt¼8.6 Hz, Jd¼4.3 Hz), 4.12e4.18 (m, 1 H), 4.27 (td, 1 H, Jt¼6.9 Hz, Jd¼4.0 Hz), 5.67 (ddd, 1 H, J¼5.5, 3.9, 1.8 Hz), 7.45e7.48 (m, 2 H), 7.57e7.61 (m, 1 H), 8.02e8.05 (m, 2 H). 13C NMR (CDCl3, 100 MHz) d 28.7, 33.7, 67.1, 74.5, 81.2, 128.5, 129.6, 129.7, 133.4, 165.6. HRMS (EIþ) m/z 286.0028/284.0063 [Mþ]; calculated mass for C12H13O3Brþ: 286.0028/284.0048. Anal. Calcd for C12H13O2Br (285.13): C, 50.55; H, 4.60; found: C, 50.20; H, 4.65. rel-(3S,4R)-3-Bromotetrahydropyran-4-yl benzoate cis-(11c). Yield (determined vs para-bromobenzaldehyde as internal NMR-standard): 16.5 mg (58 mmol, 6%), orange oil. Rf¼0.33 [diethyl ether/pentane¼1:2 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 2.00e2.07 (m, 1 H), 2.17e2.30 (m, 1 H), 3.74 (ddd, 1 H, J¼11.7, 6.3, 4.0 Hz), 3.91e3.96 (m, 1 H), 3.98e4.04 (m, 1 H), 4.05e4.10 (m, 1 H), 4.43 (dt, 1 H, Jd¼7.0 Hz, Jt¼3.3 Hz), 5.35 (dt, 1 H, Jd¼6.9 Hz, Jt¼3.3 Hz), 7.45e7.50 (m, 2 H), 7.58e7.62 (m, 1 H), 8.09e8.12 (m, 2 H). 13C NMR (CDCl3, 100 MHz) d 30.0, 49.1, 64.2, 69.5, 69.6, 128.5, 129.67, 129.74, 133.3, 165.4. HRMS (EIþ) m/z 205.0870 [MþBr]; calculated mass for C12H13Oþ 3 : 205.0865. 4.3.6. Conversion of 3-[(2R,3S)-2,3-bis-(acetyloxy)pent-4-en-1-oxy]4-methylthiazole-2(3H)-thione erythro-(1d). Reactants: 3-[(2R,3S)2,3-bis-(acetyloxy)pent-4-en-1-oxy]-4-methylthiazole-2(3H)-thione erythro-(1d) (320 mg, 966 mmol), bromotrichloromethane (0.82 mL, 8.32 mmol), AIBN (40 mg, 0.24 mmol) in a,a,a-trifluorotoluene (3 mL) according to procedure 4.3.2. 4-Methyl-2(trichloromethylsulfanyl)thiazole (2). Yield: 119 mg (478 mmol, 49%), yellow oil. Rf¼0.55 [pentane/diethyl ether¼1:2 (v/v)]. NMR data agreed with values from an authentic sample. (2S,3R,4R)-2-Bromomethyltetrahydrofuran-3,4-diyl bisacetate ciserythro-(3d). Yield: 103 mg (365 mmol, 38%), yellow oil. Rf¼0.55 [petroleum ether/ diethyl ether¼1:2 (v/v)]. 1H NMR (400 MHz, C6D6) d 1.56 (s, 3 H), 1.65 (s, 3 H), 3.19 (d, 2 H, J¼7.0 Hz), 3.58e3.65 (m, 2 H), 3.80 (td, 1 H, Jt¼7.0 Hz, Jd¼4.8 Hz), 5.09 (td, 1 H, Jt¼6.2 Hz, Jd¼5.1 Hz), 5.29 (t, 1 H, J¼4.9 Hz). 13C NMR (100 MHz, C6D6) d 20.28, 20.33, 29.2, 69.7, 71.9, 72.2, 79.2, 169.2, 169.5. MS (EI) m/z 283 (1), 281 (1), 201 (26), 187 (76), 178 (5), 158 (17), 141 (42), 127 (37), 115 (100), 99 (20), 85 (45), 81 (77). (2R,3R,4R)-2-Bromomethyltetrahydrofuran-3,4-diyl bisacetate transerythro-(3d). Yield: 43.3 mg (154 mmol, 16%), yellow oil. Rf¼0.55 [petroleum ether/diethyl ether¼1:2 (v/v)]. 1H NMR (400 MHz, C6D6) d 1.62 (s, 3 H), 1.63 (s, 3 H), 3.03e3.14 (m, 2 H), 3.57e3.65 (m, 1 H), 3.74 (dd, 1 H, J¼10.2, 4.8 Hz), 3.98 (dt, 1 H, Jd¼6.6 Hz, Jt¼4.5 Hz), 5.14 (dd, 1 H, J¼6.6, 5.3 Hz), 5.23 (td, 1 H, Jt¼5.0 Hz, Jd¼3.5 Hz). 13C NMR (100 MHz, C6D6) d 20.4, 20.5, 33.3, 71.1, 72.3, 74.5, 79.6, 169.5, 169.6. MS (EI) m/z 283(1), 281(1), 201(14), 187(33), 141(50), 127(21), 115 (100), 99(12), 85(24), 81(41). Mixture of ciserythro- and transerythro-(3d): HRMS (EIþ) m/z 283.0065/281.0023 [MþH]þ; calculated mass for C9H14O5Brþ: 283.0004/281.0025; m/z 201.0767 [MþH]þBr; calculated mass for C9H13Oþ 5 : 201.0763. Anal. Calcd for C9H13BrO5 (281.17): C, 38.66; H, 4.66; found: C, 38.64; H, 4.96. (3R,4R,5R)-3-Bromotetrahydropyran4,5-diyl bisacetate transerythro-(11d). Yield: 24.6 mg (87.5 mmol, 9%), yellow oil. Rf¼0.55 [petroleum ether/diethyl ether¼1:2 (v/v)]. 1H NMR (400 MHz, C6D6) d 1.65 (s, 3 H), 1.73 (s, 3 H), 2.80 (dd, 1 H, J¼13.1, 1.1 Hz), 3.07 (t, 1 H, J¼11.2 Hz), 3.50e3.54 (m, 1 H), 3.85 (ddd, 1 H, J¼11.6, 4.9, 1.1 Hz), 4.12 (td, 1 H, Jt¼10.8 Hz, Jd¼5.0 Hz), 5.03 (dd, 1 H, J¼10.6, 3.5 Hz), 5.21e5.22 (m, 1 H). 13C NMR (100 MHz, C6D6) d 20.57, 20.65, 45.3, 68.7, 70.0, 71.6, 74.1, 169.6, 169.9. MS (EI) m/z 283 (1), 281 (1), 237 (5), 195 (17), 179 (5), 159 (5), 141 (100), 140 (29), 115 (4), 103 (12), 99 (66), 98 (58), 81 (17). (3S,4R,5R)-3-Bromotetrahydropyran-4,5-diyl bisacetate ciserythro-(11d). Yield: 10.6 mg (37.9 mmol, 4%), yellow oil. Rf¼0.55 [petroleum ether/diethyl ether¼1:2 (v/v)]. 1H NMR (400 MHz, C6D6) d 1.60 (s, 3 H), 1.72 (s,

3 H), 3.32e3.37 (m, 1 H), 3.38e3.44 (m, 1 H), 3.47e3.49 (m, 2 H), 3.51e3.55 (m, 1 H), 4.82 (ddd, 1 H, J¼10.7, 5.3, 2.8 Hz), 5.62e5.64 (m, 1 H). 13C NMR (100 MHz, C6D6) d 20.48, 20.50, 44.3, 63.9, 67.5, 68.1, 69.5, 169.2, 169.6. MS (EI) m/z 283 (1), 281 (1), 222 (1), 209 (4), 207 (4), 195 (3), 178 (7), 177 (7), 159 (15), 141 (100), 140 (56), 103 (38), 99 (90), 98 (59), 81 (20). Mixture of ciserythro- and transerythro-(11d): HRMS (EIþ) m/z 283.0043/281.0040 [MþH]þ; calculated mass for C9H14O5Brþ: 283.0004/281.0025; m/z 238.9760/236.9976 [MþC2H3O]; calculated mass for C7H10O4Brþ: 238.9742/236.9762. 4.3.7. Conversion of 3-[(2S,3S)-bis(acetyloxy)pent-4-en-1-oxy]-4methylthiazole-2(3H)-thione threo-(1d). Reactants: 3-[(2S,3S)Bis(acetyloxy)pent-4-en-1-oxy]-4-methylthiazole-2(3H)-thione threo-(1d) (200 mg, 603 mmol), bromotrichloromethane (0.55 mL, 5.58 mmol), AIBN (25 mg, 0.15 mmol) in a,a,a-trifluorotoluene (2 mL) according to procedure 4.3.2. 4-Methyl-2-(trichloromethylsulfanyl) thiazole (2). Yield: 97.0 mg (390 mmol, 65%), yellow oil. Rf¼0.55 [pentane/diethyl ether¼1:2 (v/v)]. NMR data agreed with values from an authentic sample. (2S,3R,4S)-2-Bromomethyltetrahydrofuran-3,4diyl bisacetate cisthreo-(3d). Yield: 38.3 mg (136 mmol, 22%), yellow oil. Rf¼0.56 [petroleum ether/methyl tert-butyl ether¼1:4 (v/v)]. 1H NMR (400 MHz, C6D6) d 1.48 (s, 3 H), 1.50 (s, 3 H), 3.16 (d, 2 H, J¼7.3 Hz), 3.58 (dd, 1 H, J¼10.5, 2.3 Hz), 4.00 (dd, 1 H, J¼10.7, 4.9 Hz), 4.14 (td, 1 H, Jt¼7.0 Hz, Jd¼3.8 Hz), 5.07e5.09 (m, 1 H), 5.37 (dd, 1 H, J¼3.7, 1.0 Hz). 13C NMR (100 MHz, C6D6) d 20.3, 20.5, 28.0, 72.7, 76.4, 77.9, 80.2, 169.1, 169.4. MS (EI) m/z 283 (1), 281 (1), 201 (10), 187 (8), 178 (2), 158 (3), 141 (18), 127 (10), 115 (100), 99 (8), 85 (17), 81 (58). (2R,3R,4S)-2-Bromomethyltetrahydrofuran-3,4-diyl bisacetate transthreo-(3d). Yield: 38.2 mg (136 mmol, 22%), yellow oil. Rf¼0.56 [petroleum ether/methyl tert-butyl ether¼1:4 (v/v)]. 1H NMR (400 MHz, C6D6) d 1.49 (s, 3 H), 1.50 (s, 3 H), 3.27e3.36 (m, 2 H), 3.69e3.72 (m, 1 H), 3.78e3.81 (m, 1 H), 3.86 (td, 1 H, Jt¼5.9 Hz, Jd¼3.5 Hz), 5.07 (dt, 1 H, Jd¼4.3 Hz, Jt¼1.6 Hz), 5.17e5.19 (m, 1 H). 13C NMR (100 MHz, C6D6) d 20.4, 20.5, 32.2, 72.5, 78.4, 80.2, 83.9, 169.5, 169.7. Mixture of cisthreo- and transthreo-3d: HRMS (EIþ) m/z 283.0000/281.0010 [MþH]þ; calculated mass for C9H14O5Brþ: 283.0004/281.0025; m/z 187.0623 [MþCH3Br]; calculated mass for C8H11Oþ 5 : 187.0606. Anal. Calcd for C9H13BrO5 (281.17): C, 38.66; H, 4.66; found: C, 38.66; H, 4.90. (3R,4R,5S)-4,5-Bis(acetyloxy)-3-bromomethyltetrahydropyran transthreo-(11d). Yield: 8.09 mg (28.8 mmol, 2%), yellow oil. Rf¼0.56 [petroleum ether/methyl tert-butyl ether¼1:4 (v/v)]. 1H NMR (600 MHz, CDCl3) d 2.11 (s, 3 H), 2.12 (s, 3 H), 3.31 (t, 1 H, J¼10.7 Hz), 3.50 (t, 1 H, J¼11.4 Hz), 3.83e3.91 (m, 1 H), 4.08e4.11 (m, 1 H), 4.14 (dd, 1 H, J¼11.6, 5.0 Hz), 4.89 (ddd, 1 H, J¼10.3, 9.2, 5.5 Hz), 5.21 (t, 1 H, J¼9.6 Hz). 13C NMR (CDCl3, 150 MHz) d 20.8, 20.9, 44.7, 67.8, 69.9, 71.2, 75.2, 169.4, 169.5. (3R,4R,5S)-4,5-Bisacetyloxy-3-bromomethyltetrahydropyran cisthreo-(11d). Yield: 3.75 mg (13.3 mmol, 5%), yellow oil. Rf¼0.56 [petroleum ether/methyl tert-butyl ether¼1:4 (v/v)]. 1H NMR (600 MHz, CDCl3) d 2.11 (s, 3 H), 2.12 (s, 3 H), 3.70 (dd, 1 H, J¼12.7, 3.9 Hz), 3.83e3.91 (m, 3 H), 4.47 (ddd, 1 H, J¼8.2, 4.3, 3.5 Hz), 4.95e4.97 (m, 1 H), 5.13e5.15 (m, 1 H). 13C NMR (150 MHz, CDCl3) d 20.8, 20.9, 45.3, 65.8, 68.2, 68.7, 69.1, 169.4, 169.5. 4.3.8. Conversion of 3-[(2S,3S,4S)-3,4-O-bis(acetyloxy)hex-5-en-2oxy]-4-methyl-5-(p-methoxyphenyl)thiazole-2(3H)-thione (1e). Reactants: 3-[(2S,3S,4S)-3,4-O-Bis(acetyloxy)hex-5-en-2oxy]-4-methyl-5-(p-methoxyphenyl)thiazole-2(3H)-thione (1e) (222 mg, 0.49 mmol), bromotrichloromethane (488 mL, 4.9 mmol), AIBN (20 mg, 0.12 mmol) in benzene (5 mL) according to procedure 4.3.1. Reaction time: 2.5 h. Eluent used for chromatographic purification: diethyl ether/pentane¼1/1 (v/v). 4-Methyl-5-(p-methoxyphenyl)-2-(trichloromethylsulfanyl)thiazole (12). Yield: 96.9 mg (0.27 mmol, 55%), yellow crystals. Rf¼0.48 [diethyl ether/ pentane¼1/1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 2.57 (s, 3 H), 3.85 (s, 3 H), 6.97 (d, 2 H, J¼8.6 Hz), 7.24 (d, J¼8.6 Hz). 13C NMR (150 MHz, C6D6) d 16.3, 54.9, 97.9, 114.6, 123.4, 129.9, 130.7, 141.6,

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150.1, 150.8, 160.4. MS (EI) m/z 355 [Mþ], 248 (8), 236 (100), 203 (28), 192 (17), 177 (38), 160 (22), 145 (27), 134 (8), 119 (5), 108 (9), 77 (8).24 (2S,3R,4R,5R)-5-Bromo-2-methyltetrahydropyran-3,4-diyl bisacetate trans-(11e). Yield: 12.0 mg (40.8 mmol, 8%), yellow crystals. Rf¼0.36 [diethyl ether/pentane¼1/1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.14 (d, 3 H, J¼6.4 Hz), 2.05 (s, 3 H), 2.16 (s, 3 H), 3.57e3.64 (m, 1 H), 3.74e3.79 (q, 1 H, J¼6.7 Hz), 4.14e4.21 (m, 2 H), 5.03 (dd, 1 H, J¼3.5, 10.8 Hz), 5.22 (dd, 1 H, J¼1.0, 3.2 Hz). 13C NMR (CDCl3, 100 MHz) d 16.6, 20.6, 20.7, 44.0, 71.3, 71.9, 74.0, 74.7, 169.8, 170.4. MS (EI) m/z 207/209 (4), 152/154 (24), 129 (22), 113 (75), 103 (14), 95 (16), 85 (16), 69 (100), 57 (13). 2-Brommethyl-5-methyltetrahydrofuran-3,4-diyl bisacetate (3e). Yield: 72.7 mg (247 mmol, 50%, 2,5-cis:2,5-trans ¼ 30:70), yellow oil. Rf¼0.24 [diethyl ether/ pentane¼1/1 (v/v)]. cis-3e: 1H NMR (CDCl3, 600 MHz) d 1.21 (d, 3 H, J¼6.9 Hz), 2.09 (d, 6 H, J¼2.2 Hz), 3.41e3.45 (m, 2 H), 4.17e4.29 (m, 2 H), 4.37e4.42 (m, 1 H), 5.36e5.40 (m, 1 H), 5.51 (t, 1 H, J¼5.5 Hz). 13 C NMR (CDCl3, 100 MHz) d 15.4, 20.5, 20.9, 29.4, 72.4, 72.9, 75.3, 77.9, 169.6, 169.8. MS (EI) m/z 201 (15), 175/177 (19), 155 (93), 129 (58), 113 (18), 99 (100), 95 (60), 87 (16), 69 (39), 57 (17). trans-3e: 1H NMR (CDCl3, 600 MHz) d 1.23 (d, 3 H, J¼1.9 Hz), 2.04 (s, 3 H), 2.12 (s, 3 H), 3.49 (dd, 1 H, J¼4.4, 11.1 Hz), 3.59 (dd, 1 H, J¼4.4, 11.1 Hz), 4.17e4.29 (m, 1 H), 4.37e4.42 (m, 1 H), 5.29e5.32 (m, 1 H), 5.36e5.40 (m, 1 H). 13C NMR (CDCl3, 100 MHz) d 14.8, 20.6 (2C), 33.7, 73.6, 74.9, 76.1, 78.1, 169.8, 170.4. MS (EI) m/z 201 (15), 175/177 (19), 155 (93), 129 (58), 113 (18), 99 (100), 95 (60), 87 (16), 69 (39), 57 (17). Mixture of cis- and trans-3e: Anal. Calcd for C10H15BrO5 (295.13): C, 40.70; H, 5.12; found: C, 41.02; H, 5.13. (2S,3R,4R,5S)-5Bromo-2-methyltetrahydropyran-3,4-diyl bisacetate cis-(11e). Yield: 3.03 mg (10.3 mmol, 2%), yellow oil. Rf¼0.12 [diethyl ether/ pentane¼1/1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.26 (d, 3 H, J¼6.7 Hz), 2.10 (s, 3 H), 2.17 (s, 3 H), 3.74e3.79 (m, 1 H), 3.93e3.98 (m, 1 H), 4.24e4.28 (m, 2 H), 5.09 (t, 1 H, J¼4.0 Hz), 5.15 (t, 1 H, J¼2.5 Hz). 13C NMR (CDCl3, 100 MHz) d 16.3, 20.9 (2C), 44.6, 68.9, 69.1, 70.3, 73.6, 170.0, 170.7. MS (EI) m/z 207/209 (4), 152/154 (24), 129 (22), 113 (75), 103 (14), 95 (16), 85 (16), 69 (100), 57 (13). 4.3.9. Conversion of rel-(3R,5S)-3-(3-hydroxynona-1,8-dien-5-oxy)4-methylthiazole-2(3H)-thione (1f) with Bu3SnH. A solution of rel(3R,5S)-3-(3-hydroxynona-1,8-dien-5-oxy)-4-methylthiazole2(3H)-thione (1f) (418 mg, 1.46 mmol) in benzene (17.0 mL) containing tributylstannane (1.57 g, 5.40 mmol) and AIBN (59.9 mg, 0.37 mmol) was boiled under reflux for 2 h, while being heated in an oil bath (bath temperature 100  C). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure (200 mbar, 40  C), to leave a residue which was purified by chromatography [SiO2, diethyl ether/pentane¼1:2 (v/ v)]. 4-Methyl-2-(tributylstannylsulfanyl)thiazole (13). Yield: 1.15 mmol (79%, yield was determined via 1H NMR with pentachlorobenzene as internal standard before the chromatography). 1H NMR (CDCl3, 200 MHz): d 0.87e0.94 (m, 9 H), 1.24e1.68 (m, 18 H), 2.28 (s, 3 H), 6.54 (s, 1 H). rel-(20 S,2R)-1-(50 -methyltetrahydrofuran20 -yl)but-3-ene-2-ol (15). Yield: 127 mg (815 mmol, 56%), as a mixture of cis- and trans-isomers (A:B¼27:73), colorless liquid. Rf¼0.23 [diethyl ether/pentane¼1:2 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.21 (dd, 3 H, J¼6.1, 0.7 Hz, B), 1.24 (dd, 3 H, J¼6.1, 0.7 Hz, A), 1.40e1.70 (m, 4 H, A/B), 1.91e2.07 (m, 2 H, B), 2.09e2.16 (m, 2 H, A), 4.00e4.07 (m, 1 H, B), 4.11e4.18 (m, 1 H, B), 4.21e4.27 (m, 2 H, A), 4.31e4.35 (m, 1 H, A/B), 5.07 (d, 1 H, J¼10.4 Hz, A/B), 5.27 (d, 1 H, J¼17.2 Hz, A/ B), 5.80e5.89 (m, 1 H, A/B). 13C NMR (CDCl3, 100 MHz) d 21.1, 21.4, 32.1, 32.2, 33.0, 33.2, 42.6, 43.2, 72.8, 72.9, 75.1, 76.2, 79.0, 79.6, 114.0 (2C), 140.5 (2C). Retention time (tr)¼12.2 min (for GC/MS conditions see Supplementary data): MS (EI) m/z 138 (10), 127 (5), 111 (5), 98 (14), 85 (100), 79 (110), 67 (33), 57 (52). HRMS (EIþ) m/z 156.1146 [Mþ]; calculated mass for C9H16Oþ 2 : 156.1150. tr¼12.3 min: MS (EI) m/z 138 (10), 127 (5), 111 (5), 98 (14), 85 (100), 79 (110), 67

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(33), 57 (52). HRMS (EIþ) m/z 156.1135 [Mþ]; calculated mass for C9H16Oþ 2 : 156.1150. rel-(3R,5S)-5-(But-3-en-1-yl)-2-methyltetrahydrofuran-3-ol (14) and Tetrahydropyran-derivative as a 86/14mixture. Yield: 53 mg (340 mmol, 23%), colorless liquid. Rf¼0.15 [diethyl ether/pentane¼1:1 (v/v)]. rel-(3R,5S)-5-(But-3-en-1-yl)-2methyltetrahydrofuran-3-ol (14) as a mixture of cis- and trans-isomers (A:B¼20:80). Main isomer B: 1H NMR (CDCl3, 400 MHz) d 1.23 (d, 3 H, J¼6.3 Hz), 1.46e1.78 (m, 4 H), 2.02e2.20 (m, 2 H), 3.95e4.00 (m, 1 H), 4.14e4.17 (m, 1 H), 4.19e4.24 (m, 1 H), 4.93e5.10 (m, 2 H), 5.76e5.90 (m, 1 H). 13C NMR (CDCl3, 100 MHz) d 14.2, 30.2, 35.4, 41.6, 74.1, 76.5, 77.3, 114.6, 138.2. Retention time (tr)¼12.8 min: MS (EI) m/z 138 (1), 127 (14), 114 (57), 101 (57), 79 (29), 70 (29), 57 (100), 53 (10). HRMS (EIþ) m/z 156.1151 [Mþ]; calculated mass for þ C9H16Oþ 2 : 156.1150; m/z 138.1042 [M H2O]; calculated mass for C9H14Oþ : 138.1045. Minor isomer A: t 1 r¼12.6 min: MS (EI) m/z 138 (1), 127 (14), 114 (57), 101 (57), 79 (29), 70 (29), 57 (100), 53 (10). HRMS (EIþ) m/z 138.1036 [MþH2O]; calculated mass for C9H14Oþ 1: 138.1045. Tetrahydropyran-derivative. Retention time (tr)¼13.6 min: MS (EI) m/z 137 (0.9), 114 (10), 101 (14), 83 (28), 79 (19), 67 (48), 55 (100), 51 (10). HRMS (EIþ) m/z 138.1042 [MþH2O]; calculated mass for C9H14Oþ 1 : 138.1045. 4.4. Reduction of bromomethyletrahydrofurans 4.4.1. General method. Tributylstannane (1.03 g, 3.40 mmol) and AIBN (25.0 mg, 0.15 mmol) were added to a solution of 2bromomethyltetrahydrofuran-3-yl acetate (3b) (303 mg, 1.36 mmol) in dry benzene (20 mL). The reaction mixture was boiled under reflux for 1.5 h and treated afterwards at room temperature with potassium fluoride (2.5 g, 43.0 mmol) and water (2 mL). Stirring was continued for 30 min at room temperature. The slurry was dried (MgSO4) and filtrated. The solids were washed with methyl tert-butyl ether (330 mL). Organic washings were combined with the filtrate from potassium fluoride-treatment and concentrated under reduced pressure (300 mbar, 40  C). The remaining oil was purified by chromatography [SiO2, diethyl ether/ pentane¼2:1 (v/v)]. 4.4.2. cis-2-Methyltetrahydrofuran-3-yl acetate cis-(16). From cis-2bromomethyltetrahydrofuran-3-yl acetate cis-(3b) according to procedure 4.4.1. Yield: 114 mg (790 mmol, 58%), yellowish oil. Rf¼0.52 [diethyl ether/pentane¼2:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.21 (d, 3 H, J¼6.5 Hz), 1.90e2.01 (m, 1 H), 2.08 (s, 3 H), 2.25e2.36 (m, 1 H), 3.75 (td, 1 H, Jt¼8.7 Hz, Jd¼6.5 Hz), 3.83e3.96 (m, 1 H), 4.02 (q, 1 H, J¼8.2 Hz), 5.26 (ddd, 1 H, J¼6.0, 4.0, 1.9 Hz). 13C NMR (CDCl3, 150 MHz) d 14.1, 20.9, 33.4, 65.8, 75.2, 77.3, 170.6.67 4.4.3. trans-2-Methyltetrahydrofuran-3-yl acetate trans-(16). From trans-2-bromomethyltetrahydrofuran-3-yl acetate trans-(3b) according to procedure 4.4.1. Yield: 120 mg (830 mmol, 61%), yellowish oil. Rf¼0.55 [diethyl ether/pentane¼2:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) d 1.23 (d, 3 H, J¼6.5 Hz), 1.85e1.98 (m, 1 H), 2.06 (s, 3 H), 2.16e2.27 (m, 1 H), 3.79e4.04 (m, 3 H), 4.86 (dt, 1 H, Jd¼6.5 Hz, Jt¼2.4 Hz). 13C NMR (CDCl3, 150 MHz) d 19.0, 21.1, 32.0, 66.5, 79.6, 80.0, 170.3.67 Supplementary data Supplementary data (Instrumentation, precursors for the synthesis of 3-alkenoxythiazole-2(3H)-thiones 1aef (alkenols and alkenyl p-toluenesulfonates), 1H NMR- and 13C NMR spectra of selected 3-alkenoxythiazole-2(3H)-thiones, tetrahydrofurans and tetrahydropyrans (30 pages).) related to this article can be found at http://dx.doi.org/10.1016/j.tet.2016.07.001.

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